Volume 21 Supplement 1
37th International Symposium on Intensive Care and Emergency Medicine (part 3 of 3)
- M. Von Seth1,
- L. Hillered1,
- A. Otterbeck1,
- K. Hanslin1,
- A. Larsson1,
- J. Sjölin1,
- M. Lipcsey1,
- ME Cove2,
- N. S. Chew3,
- L. H. Vu3,
- R. Z. Lim3,
- Z. Puthucheary4,
- K. Hanslin5,
- F. Wilske6,
- P. Skorup6,
- E. Tano6,
- J. Sjölin6,
- M. Lipcsey5,
- I. Derese7,
- S. Thiessen7,
- S. Derde7,
- T. Dufour7,
- L. Pauwels7,
- Y. Bekhuis7,
- G. Van den Berghe7,
- I. Vanhorebeek7,
- M. Khan8,
- D. Dwivedi8,
- J. Zhou8,
- A. Prat9,
- N. G. Seidah9,
- P. C. Liaw8,
- A. E. Fox-Robichaud8,
- M. Von Seth10,
- P. Skorup10,
- L. Hillered10,
- A. Larsson10,
- J. Sjölin10,
- M. Lipcsey10,
- A. Otterbeck11,
- K. Hanslin11,
- M. Lipcsey11,
- A. Larsson11,
- M. Von Seth11,
- T. Correa12,
- J Pereira12,
- J Takala13,
- S Jakob13,
- P. Skorup14,
- L. Maudsdotter15,
- E. Tano14,
- M. Lipcsey16,
- M. Castegren14,
- A. Larsson14,
- J Sjölin14,
- M. Xue17,
- J. Y. Xu17,
- L. Liu17,
- Y. Z. Huang17,
- F. M. Guo17,
- Y. Yang17,
- H. B. Qiu17,
- A. Kuzovlev18,
- V. Moroz18,
- A. Goloubev18,
- A. Myazin18,
- A. Chumachenko18,
- V. Pisarev18,
- N. Takeyama19,
- M. Tsuda19,
- H. Kanou19,
- R. Aoki19,
- Y. Kajita19,
- M. Hashiba19,
- T. Terashima19,
- A. Tomino19,
- R. Davies20,
- K. P. O’Dea20,
- S. Soni20,
- J. K. Ward20,
- D. J. O’Callaghan20,
- M. Takata20,
- A. C. Gordon20,
- J. Wilson21,
- Y. Zhao21,
- M. Singer22,
- J. Spencer21,
- M. Shankar-Hari21,
- K. Roveran Genga23,
- C. Lo23,
- M. S. Cirstea23,
- K. R. Walley23,
- J. A. Russell23,
- A. Linder24,
- J. H. Boyd23,
- A. Sedlag25,
- C. Riedel25,
- M. Georgieff26,
- E. Barth26,
- H. Bracht26,
- A. Essig26,
- D. Henne-Bruns26,
- F. Gebhard26,
- K. Orend26,
- M. Halatsch26,
- M. Weiss26,
- M. Chase27,
- E. Freinkman28,
- A. Uber27,
- X. Liu27,
- M. N. Cocchi27,
- M. W. Donnino27,
- M. Peetermans29,
- L. Liesenborghs30,
- J. Claes30,
- T. Vanassche30,
- M. Hoylaerts30,
- M. Jacquemin30,
- K. Vanhoorelbeke30,
- S. De Meyer30,
- P. Verhamme29,
- A. Vögeli31,
- M. Ottiger31,
- M. Meier31,
- C. Steuer31,
- L. Bernasconi31,
- A. Huber31,
- M. Christ-Crain32,
- C. Henzen33,
- C. Hoess34,
- R. Thomann35,
- W. Zimmerli33,
- B. Müller31,
- P. Schütz31,
- D. Hoppensteadt36,
- A. Walborn36,
- M. Rondina37,
- K. Tsuruta38,
- J. Fareed36,
- S. Tachyla39,
- T. Ikeda40,
- S. Ono40,
- T. Ueno40,
- S. Suda40,
- T. Nagura40,
- E. Damiani41,
- R. Domizi41,
- C. Scorcella41,
- S. Tondi41,
- S. Pierantozzi41,
- S. Ciucani41,
- N. Mininno41,
- E. Adrario41,
- P. Pelaia41,
- A. Donati41,
- M. Schou Andersen42,
- S. Lu42,
- G Lopez42,
- AT Lassen43,
- I. Ghiran42,
- N. I. Shapiro42,
- U. Trahtemberg44,
- S. Sviri44,
- M. Beil45,
- Z. Agur46,
- P. Van Heerden44,
- E. Jahaj47,
- A. Vassiliou47,
- Z. Mastora47,
- S. E. Orfanos48,
- A. Kotanidou47,
- Y. Wirz49,
- R. Sager49,
- D. Amin50,
- A. Amin50,
- S. Haubitz49,
- P. Hausfater51,
- A. Huber49,
- A. Kutz49,
- B. Mueller49,
- P. Schuetz49,
- R. S. Sager52,
- Y. W. Wirz52,
- D. A. Amin53,
- A. A. Amin53,
- P. H. Hausfater54,
- A. H. Huber52,
- S. Haubitz52,
- A. Kutz52,
- B Mueller52,
- P Schuetz52,
- L. Gottin55,
- C. Dell’amore55,
- G. Stringari55,
- G. Cogo55,
- M. Ceolagraziadei55,
- M. Sommavilla55,
- F. Soldani55,
- E. Polati55,
- M. Meier56,
- T. Baumgartner56,
- G. Zurauskaité56,
- S. Gupta57,
- B. Mueller56,
- A. Devendra57,
- P. Schuetz56,
- D. Mandaci58,
- G. Eren58,
- F. Ozturk58,
- N. Emir58,
- O. Hergunsel58,
- S. Azaiez59,
- S. Khedher59,
- A. Maaoui59,
- M. Salem59,
- E. Chernevskaya60,
- N. Beloborodova60,
- A. Bedova60,
- Y. U. Sarshor60,
- A. Pautova60,
- V. Gusarov61,
- N. Öveges62,
- I. László62,
- M. Forgács62,
- T. Kiss62,
- P. Hankovszky62,
- P. Palágyi62,
- A. Bebes62,
- B. Gubán62,
- I. Földesi62,
- Á. Araczki62,
- M. Telkes62,
- Z. Ondrik62,
- Z. Helyes63,
- Á. Kemény63,
- Z. Molnár62,
- E. Spanuth64,
- H. Ebelt65,
- B. Ivandic64,
- R. Thomae66,
- K. Werdan65,
- M. El-Shafie67,
- K. Taema67,
- M. El-Hallag67,
- A. Kandeel68,
- O. Tayeh69,
- K. Taema69,
- M. Eldesouky69,
- A. Omara70,
- M. S. Winkler71,
- M. Holzmann71,
- A. Nierhaus72,
- E. Mudersbach73,
- E. Schwedhelm73,
- G. Daum74,
- S. Kluge74,
- C. Zoellner71,
- G. Greiwe75,
- H. Sawari76,
- E. Schwedhelm77,
- A. Nierhaus78,
- S. Kluge78,
- J. Kubitz75,
- R. Jung79,
- G. Daum80,
- H. Reichenspurner76,
- C. Zoellner75,
- M. S. Winkler75,
- M. Groznik81,
- A. Ihan82,
- L. W. Andersen83,
- M. Chase83,
- M. J. Holmberg83,
- A. Wulff83,
- M. N. Cocchi83,
- M. W. Donnino83,
- C. Balci84,
- M. Haliloglu85,
- B. Bilgili85,
- H. Bilgin85,
- U. Kasapoglu85,
- I. Sayan85,
- M. Süzer85,
- L. Mulazımoglu85,
- I. Cinel85,
- V. Patel86,
- S. Shah86,
- P. Parulekar86,
- C. Minton87,
- J. Patel87,
- C. Ejimofo87,
- H. Choi87,
- R. Costa88,
- P. Caruso88,
- P. Nassar88,
- J. Fu89,
- J. Jin89,
- Y. Xu89,
- J. Kong89,
- D. Wu89,
- A. Yaguchi90,
- A. Klonis91,
- S. Ganguly91,
- M. Kollef92,
- C. Burnham92,
- B. Fuller92,
- A. Mavrommati93,
- D. Chatzilia93,
- E. Salla93,
- E. Papadaki93,
- S. Kamariotis93,
- S. Christodoulatos93,
- A. Stylianakis93,
- G. Alamanos93,
- M. Simoes94,
- E. Trigo94,
- N. Silva94,
- P. Martins94,
- J. Pimentel94,
- D. Baily95,
- L. A. Curran96,
- E. Ahmadnia96,
- B. V. Patel96,
- D. Adukauskiene97,
- J Cyziute98,
- A. Adukauskaite99,
- D. Pentiokiniene97,
- F. Righetti100,
- E. Colombaroli100,
- G. Castellano100,
- F. Wilske101,
- P. Skorup101,
- M. Lipcsey102,
- K. Hanslin102,
- A. Larsson101,
- J. Sjölin101,
- M. Man103,
- H. P. Shum103,
- Y. H. Chan103,
- K. C. Chan104,
- W. W. Yan103,
- R. A. Lee105,
- S. K. Lau106,
- P. Dilokpattanamongkol107,
- P. Thirapakpoomanunt107,
- R. Anakkamaetee107,
- P. Montakantikul107,
- V. Tangsujaritvijit108,
- S. Sinha109,
- J. Pati109,
- S. Sahu109,
- D. Adukauskiene110,
- D. Valanciene110,
- A. Dambrauskiene110,
- D. Adukauskiene111,
- D. Valanciene111,
- A. Dambrauskiene111,
- K. Hernandez112,
- T. Lopez112,
- D. Saca112,
- M. Bello112,
- W. Mahmood113,
- K. Hamed113,
- N. Al Badi113,
- S. AlThawadi113,
- S. Al Hosaini113,
- N. Salahuddin113,
- C. C. Cilloniz114,
- A. C. Ceccato114,
- G. L. Li Bassi114,
- M. F. Ferrer114,
- A. G. Gabarrus114,
- O. R. Ranzani114,
- A. S. San Jose114,
- C. G. Garcia Vidal114,
- J. P. Puig de la Bella Casa114,
- F. B. Blasi115,
- AT Torres114,
- D. Adukauskiene116,
- A. Ciginskiene116,
- A. Dambrauskiene117,
- R. Simoliuniene118,
- G. Giuliano119,
- D. Triunfio119,
- E. Sozio119,
- E. Taddei119,
- E. Brogi119,
- F. Sbrana120,
- A. Ripoli120,
- G. Bertolino119,
- C. Tascini121,
- F. Forfori119,
- C. Fleischmann122,
- D. Goldfarb123,
- P. Schlattmann122,
- L. Schlapbach124,
- N. Kissoon125,
- N. Baykara126,
- H. Akalin127,
- M. Kemal Arslantas128,
- And Sepsis Study Group129,
- S. G. Gavrilovic130,
- M. V. Vukoja130,
- M. H. Hache131,
- R. K. Kashyap132,
- Y. D. Dong132,
- O. G. Gajic132,
- O. Ranzani133,
- M. Shankar-Hari134,
- D. Harrison133,
- L. Rabello135,
- K. Rowan133,
- J. Salluh135,
- M. Soares135,
- A. M. Markota136,
- J. F. Fluher136,
- D. K. Kogler136,
- Z. B. Borovšak136,
- A. S. Sinkovic136,
- I. László137,
- N. Öveges137,
- M. Forgács137,
- T. Kiss137,
- P. Hankovszky137,
- P. Palágyi137,
- A. Bebes137,
- B. Gubán137,
- I. Földesi137,
- Á. Araczki137,
- M. Telkes137,
- Z. Ondrik137,
- Z. Helyes138,
- Á. Kemény138,
- Z. Molnár137,
- J. Fareed139,
- Z Siddiqui139,
- P. Aggarwal139,
- O. Iqbal139,
- D. Hoppensteadt139,
- M. Lewis139,
- R. Wasmund139,
- S. Abro139,
- S. Raghuvir139,
- K. Tsuruta140,
- P. S. Barie141,
- D. Fineberg142,
- A. Radford142,
- K. Tsuruta142,
- A. Casazza143,
- A. Vilardo144,
- E. Bellazzi143,
- R. Boschi143,
- D. Ciprandi143,
- C. Gigliuto143,
- R. Preda143,
- R. Vanzino143,
- M. Vetere143,
- L. Carnevale143,
- E. Kyriazopoulou145,
- A. Pistiki145,
- C. Routsi145,
- I. Tsangaris145,
- E. Giamarellos-Bourboulis145,
- E. Kyriazopoulou146,
- I. Tsangaris146,
- C. Routsi146,
- I. Pnevmatikos147,
- G. Vlachogiannis148,
- E. Antoniadou149,
- K. Mandragos150,
- A. Armaganidis146,
- E. Giamarellos-Bourboulis146,
- P. Allan151,
- R. Oehmen152,
- J. Luo151,
- C. Ellis151,
- P. Latham153,
- J. Newman154,
- C. Pritchett155,
- D. Pandya155,
- A. Cripps155,
- S. Harris155,
- M. Jadav155,
- R. Langford155,
- B. Ko156,
- H. Park156,
- C. M. Beumer157,
- R. Koch157,
- D. V. Beuningen157,
- A. M. Oudelashof158,
- F. L. Vd Veerdonk157,
- E. Kolwijck157,
- J. G. VanderHoeven157,
- D. C. Bergmans158,
- C. Hoedemaekers157,
- J. B. Brandt159,
- J. Golej159,
- G. Burda159,
- G. Mostafa159,
- A. Schneider159,
- R. Vargha159,
- M. Hermon159,
- P. Levin160,
- C Broyer160,
- M. Assous160,
- Y. Wiener-Well160,
- M. Dahan160,
- S. Benenson161,
- E Ben-Chetrit160,
- A. Faux162,
- R. Sherazi162,
- A. Sethi163,
- S. Saha162,
- M. Kiselevskiy164,
- E. Gromova164,
- S. Loginov165,
- I. Tchikileva164,
- Y. Dolzhikova164,
- N. Krotenko165,
- R. Vlasenko164,
- N. Anisimova164,
- S. Spadaro166,
- A. Fogagnolo166,
- F. Remelli166,
- V. Alvisi166,
- A. Romanello166,
- E. Marangoni166,
- C. Volta166,
- A. Degrassi167,
- F. Mearelli167,
- C. Casarsa167,
- N. Fiotti167,
- G. Biolo167,
- M. Cariqueo168,
- C. Luengo168,
- R. Galvez168,
- C. Romero168,
- R. Cornejo168,
- O. Llanos168,
- N. Estuardo168,
- P. Alarcon168,
- B. Magazi169,
- S. Khan169,
- J. Pasipanodya170,
- M. Eriksson171,
- G. Strandberg171,
- M. Lipsey171,
- A. Larsson172,
- Z. Rajput173,
- F. Hiscock173,
- T. Karadag173,
- J. Uwagwu173,
- S. Jain173,
- A. Molokhia173,
- H. Barrasa174,
- A. Soraluce175,
- E. Uson174,
- A. Rodriguez175,
- A. Isla175,
- A. Martin174,
- B. Fernández174,
- F. Fonseca174,
- J. A. Sánchez-Izquierdo176,
- F. J. Maynar174,
- M. Kaffarnik177,
- R. Alraish177,
- O. Frey178,
- A. Roehr178,
- M. Stockmann177,
- S. Wicha179,
- D. Shortridge180,
- M. Castanheira180,
- H. S. Sader180,
- J. M. Streit180,
- R. K. Flamm180,
- K. Falsetta181,
- T. Lam181,
- S. Reidt181,
- J. Jancik181,
- T. Kinoshita182,
- J. Yoshimura183,
- K. Yamakawa182,
- S. Fujimi182,
- A. Armaganidis184,
- A. Torres185,
- S. Zakynthinos186,
- C. Mandragos187,
- E. Giamarellos-Bourboulis188,
- P. Ramirez189,
- M. De la Torre-Prados190,
- A. Rodriguez191,
- G. Dale192,
- A. Wach192,
- L. Beni192,
- L. Hooftman192,
- C. Zwingelstein192,
- B. François193,
- G. Colin194,
- P. F. Dequin195,
- P. F. Laterre196,
- A. Perez197,
- R. Welte198,
- I. Lorenz198,
- P. Eller199,
- M. Joannidis198,
- R. Bellmann198,
- S. Lim200,
- S. Chana200,
- S. Patel200,
- J. Higuera201,
- D. Cabestrero201,
- L. Rey201,
- G. Narváez201,
- A. Blandino201,
- M. Aroca201,
- S. Saéz201,
- R De Pablo201,
- S. Thiessen202,
- I. Vanhorebeek202,
- S. Derde202,
- I. Derese202,
- T. Dufour202,
- C. Nadège Albert202,
- L. Langouche202,
- C. Goossens202,
- N. Peersman202,
- P. Vermeersch202,
- S. Vander Perre202,
- J. Holst203,
- P. Wouters202,
- G. Van den Berghe202,
- X. Liu204,
- A. U. Uber204,
- M. Holmberg204,
- V. Konanki204,
- M. McNaughton204,
- J. Zhang204,
- M. W. Donnino204,
- O. Demirkiran205,
- A. Byelyalov205,
- C. Luengo206,
- J. Guerrero207,
- M Cariqueo206,
- C. Scorcella208,
- R. Domizi208,
- E. Damiani208,
- S. Tondi208,
- S. Pierantozzi208,
- N. Rossini208,
- U. Falanga208,
- V. Monaldi208,
- E. Adrario208,
- P. Pelaia208,
- A. Donati208,
- O. Cole209,
- N. Scawn210,
- M. Balciunas209,
- I. Blascovics209,
- A. Vuylsteke209,
- K. Salaunkey209,
- A. Omar211,
- A. Salama211,
- M. Allam211,
- A. Alkhulaifi211,
- S. Verstraete212,
- I. Vanhorebeek212,
- E. Van Puffelen213,
- I. Derese212,
- C. Ingels212,
- S. Verbruggen213,
- P. Wouters212,
- K. Joosten213,
- J. Hanot212,
- G. Guerra214,
- D. Vlasselaers212,
- J. Lin215,
- G. Van den Berghe212,
- R. Haines216,
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- R. Hewson216,
- C. Offiah216,
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- H. Buter219,
- J. A. Veenstra219,
- M. Koopmans219,
- E. C. Boerma219,
- J. A. Veenstra220,
- H. Buter220,
- M. Koopmans220,
- E. C. Boerma220,
- A. Taha221,
- A. Shafie221,
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- H. Hon221,
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- A. A. El Khattate222,
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- S. Sanaie224,
- A. Mahmoodpoor224,
- H. Hamishehkar224,
- P. Biderman225,
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- Y. Avitzur227,
- S. Solomon228,
- Z. Iakobishvili225,
- U. Carmi225,
- D Gorfil225,
- P. Singer225,
- C. Paisley229,
- J. Patrick-Heselton229,
- M. Mogk230,
- J. Humphreys231,
- I. Welters229,
- S. Pierantozzi232,
- C. Scorcella232,
- R. Domizi232,
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- E. Casarotta232,
- S. Bolognini232,
- E. Adrario232,
- P. Pelaia232,
- A. Donati232,
- M. J. Holmberg233,
- A. Moskowitz233,
- P. Patel233,
- A. Grossestreuer233,
- A. Uber233,
- L. W. Andersen233,
- M. W. Donnino233,
- S. Malinverni234,
- D. Goedeme234,
- P. Mols234,
- P. L. Langlois235,
- C. Szwec236,
- F. D’Aragon235,
- D. K. Heyland237,
- W. Manzanares238,
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- C. Szwec240,
- P. Langlois241,
- I. Aramendi239,
- D. Heyland242,
- N. Stankovic243,
- J. Nadler243,
- A. Uber243,
- M. Holmberg243,
- L. Sanchez243,
- R. Wolfe243,
- M. Chase243,
- M. Donnino243,
- M. Cocchi243,
- H. K. Atalan244,
- B. Gucyetmez245,
- M. E. Kavlak246,
- S. Aslan246,
- A. Kargi246,
- S. Yazici246,
- R. Donmez246,
- K. Y. Polat246,
- M Piechota247,
- A. Piechota248,
- M. Misztal249,
- S. Bernas247,
- I. Pietraszek-Grzywaczewska247,
- M. Saleh250,
- A. Hamdy250,
- A. Hamdy250,
- M. Elhallag250,
- F. Atar251,
- A. Kundakci251,
- E. Gedik251,
- H. Sahinturk251,
- P. Zeyneloglu251,
- A. Pirat251,
- M. Popescu252,
- D. Tomescu252,
- R. Van Gassel253,
- M. Baggerman253,
- F. Schaap254,
- M. Bol253,
- G. Nicolaes254,
- D. Beurskens254,
- S. Olde Damink253,
- M. Van de Poll253,
- M. Horibe255,
- M. Sasaki256,
- M. Sanui257,
- E. Iwasaki255,
- H. Sawano258,
- T. Goto259,
- T. Ikeura260,
- T. Hamada261,
- T. Oda262,
- T. Mayumi263,
- T. Kanai255,
- G. Kjøsen264,
- R. Horneland264,
- K. Rydenfelt264,
- E. Aandahl264,
- T. Tønnessen264,
- H. Haugaa264,
- P. Lockett265,
- L. Evans265,
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© The Author(s). 2017
Published: 21 March 2017
P349 Muscle mitochondrial function and N+/K+ -ATPase activity are unaffected by sepsis in pigs
M Von Seth, L Hillered, A Otterbeck, K Hanslin, A Larsson, J Sjölin, M Lipcsey
Uppsala University, Uppsala, Sweden
Imbalance in cellular energetics has been suggested to be an important mechanism for organ failure in sepsis and septic shock. We hypothesized that such energy imbalance would either be caused by metabolic changes leading to decreased energy production or by increased energy consumption. Thus, we set out to investigate if mitochondrial dysfunction or decreased energy consumption alters cellular metabolism in muscle tissue in experimental sepsis.
We submitted anesthetized piglets to sepsis (n = 12) or placebo (n = 4) and monitored them for 3 hours. Plasma lactate and markers of organ failure were measured hourly, as was muscle metabolism by microdialysis. Energy consumption was intervened locally by infusing ouabain through one microdialysis catheter to block major energy expenditure of the cells, by inhibiting the major energy consuming enzyme, N+/K + -ATPase. Similarly, energy production was blocked infusing sodium cyanide (NaCN), in a different region, to block the cytochrome oxidase in muscle tissue mitochondria.
All animals submitted to sepsis fulfilled sepsis criteria as defined in Sepsis-3, whereas no animals in the placebo group did. Muscle glucose decreased during sepsis independently of N+/K + -ATPase or cytochrome oxidase blockade. Muscle lactate did not increase during sepsis in naïve metabolism. However, during cytochrome oxidase blockade, there was an increase in muscle lactate that was further accentuated during sepsis. Muscle pyruvate did not decrease during sepsis in naïve metabolism. During cytochrome oxidase blockade, there was a decrease in muscle pyruvate, independently of sepsis. Lactate to pyruvate ratio increased during sepsis and was further accentuated during cytochrome oxidase blockade. Muscle glycerol increased during sepsis and decreased slightly without sepsis regardless of N+/K + -ATPase or cytochrome oxidase blocking. There were no significant changes in muscle glutamate or urea during sepsis in absence/presence of N+/K + -ATPase or cytochrome oxidase blockade.
These results indicate increased metabolism of energy substrates in muscle tissue in experimental sepsis. Our results do not indicate presence of energy depletion or mitochondrial dysfunction in muscle and should similar physiologic situation be present in other tissues, other mechanisms of organ failure must be considered.
P350 Pilot study showing reduced bone strength at 96 hours in rodent sepsis
ME Cove1, NS Chew2, LH Vu2, RZ Lim2, Z Puthucheary3
1National University Hospital, Singapore, Singapore; 2Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore; 3University College London, London, United Kingdom
Bone mineral density (BMD) is reduced in critical care survivors , and long-term follow up has shown increased fracture risk . It is unclear if these changes are a consequence of acute critical illness, or reduced activity afterwards. Bone health assessment during critical illness is challenging, and direct bone strength measurement is not possible. We used a rodent sepsis model to test the hypothesis that critical illness causes early reduction in bone strength and changes in bone architecture.
20 Sprague-Dawley rats (350 ± 15.8g) were anesthetised and randomised to receive cecal ligation and puncture (CLP) (50% cecum length, 18G needle single pass through anterior and posterior walls) or sham surgery (cecum mobilised, no CLP), and then returned to their cages. 10 rodents (5 CLP, 5 sham) were sacrificed at 24 hours, and the remaining 10 at 96 hours. Femur bones were harvested and bone strength testing was conducted using the Instron 5543 (Instron Corp, USA). Trabecular bone strength was measured using a femoral neck break and cortical bone strength tested using a femoral shaft 3-point bending test. Bone architecture was assessed using micro-computerised tomography (microCT) imaging (PerkinElmer, USA), and images analysed with BoneJ .
All 20 rats survived to the end of the protocol. The load required to fracture the femoral neck and shaft was not significantly different for CLP and sham groups at 24 hours (97 ± 19N vs 81 ± 10N p = 0.12 and 127 ± 8N vs 119 ± 18N p = 0.35, respectively). However, at 96 hours there was a significant reduction in the fracture force at both the femoral neck and shaft in the CLP group, compared to sham (75 ± 11N vs 97 ± 13N p = 0.02 and 102 ± 20N vs 139.9 ± 28N p = 0.04). In contrast, there were no bone architecture differences, as measured by bone volume/total volume, trabecular thickness/separation, connectivity density, anisotropy and BMD (all p > 0.20) using microCT at 24 or 96 hours.
In this rodent model of sepsis, there is a significant reduction in trabecular and cortical bone strength at 96 hours. In the absence of changes in bone architecture, these findings suggest sepsis may induce early biochemical changes affecting bone strength. We plan further rodent experiments to confirm these results, increase our power, assess nano-mechanics and complete a histological analysis.
1 Orford NR et al: Am J Resp Crit Care 2016,193:736–744
2 Rawal J et al: Crit Care 2015,19:165
3 Doube M et al: Bone 2010, 47:1076–1079
P351 Endotoxin clearance by the spleen is unaffected by pre-existing systemic inflammation in porcine septic shock
K Hanslin1, F Wilske2, P Skorup2, E Tano2, J Sjölin2, M Lipcsey1
1Uppsala University, Uppsala, Sweden; 2Uppsala University, Department of Medical Sciences, Uppsala, Sweden
As part of the mononuclear phagocytic system, the spleen participates in bacterial and endotoxin clearance. In our previous study we saw decreased endotoxin clearance by the liver in pigs with pre-existing systemic inflammatory response (SIR). We therefore hypothesized that immunosuppression induced by SIR may also lead to decreased trans-splenic endotoxin clearance, and set out to investigate this in a porcine model of sepsis.
15 anesthetized pigs received an [i]E. coli[/i] infusion intravenously (i.v.) for 3 hours (h). In group Pre-existing SIR (n = 6), SIR was induced by 24 h of i.v. endotoxin infusion prior to the [i]E. coli[/i] infusion. Group Non-Pre-existing SIR (n = 6) received the bacterial infusion without prior endotoxin exposure. To study the effects of 24 h of anesthesia alone, “Controls” (n = 3) received saline instead of endotoxin for 24 h prior to the bacterial infusion (not included in the primary analysis). The kinetic chromogenic LAL-test was used to analyze endotoxin in arterial and splenic venous blood samples.
All animals receiving endotoxin developed SIR prior to the [i]E. coli[/i] infusion. The amounts of [i]E. coli[/i] given to the groups were comparable. Endotoxin levels were similar at 3 h, just before the end of the [i]E. coli[/i] infusion, in the Pre-existing SIR and Non-Pre-existing SIR groups in arterial (Fig. 1) and splenic venous blood (2.40 (1.94-2.60) vs. 2.81 EU/mL (2.73-2.91) median (IQR)). Furthermore, endotoxin levels at 4 h, one hour after completed [i]E. coli[/i] infusion, were lower in Pre-existing SIR vs. Non-Pre-existing SIR group both in arterial (Fig. 1) and splenic venous blood (0.38 (0.31-0.42) vs. 0.51 EU/mL (0.47-0.71); p < 0.05). There was no difference in the ratio of splenic venous to arterial endotoxin levels between Pre-existing SIR and Non-Pre-existing SIR groups.
P352 The role of autophagy in critical illness-induced organ failure
I Derese, S Thiessen, S Derde, T Dufour, L Pauwels, Y Bekhuis, G Van den Berghe, I Vanhorebeek
University Hospital, Leuven, Belgium
Increasing evidence implicates mitochondrial dysfunction and endoplasmic reticulum (ER) stress, which activates the unfolded protein response (UPR), as contributors to critical illness-induced organ failure. Both can be alleviated by autophagy, a cellular defense mechanism. However, a phenotype of insufficiently activated autophagy has been observed during critical illness. We hypothesized that insufficient hepatic autophagy during critical illness aggravates liver damage/failure, hallmarked by mitochondrial dysfunction and ER stress.
In a centrally catheterized mouse model of critical illness, induced by cecal ligation and puncture, the effect of genetic inactivation of hepatic autophagy (via inducible deletion of autophagy gene 7 in liver) on survival, markers of organ damage, apoptosis, UPR and mitochondrial content and function was evaluated in the acute (30 hrs) and prolonged (3 days) phase. For each time point, 2 groups of critically ill mice and 2 groups of healthy pair-fed mice were included (at least 10 surviving mice per group), where each time autophagy was inactivated in one group but not in the other.
Hepatic autophagy deficiency during critical illness did not affect survival, but increased hepatic damage/dysfunction. In the acute phase, this was illustrated by higher plasma ALT (P = 0.0001), and by elevated markers of apoptosis (P = 0.001) and more mitochondrial dysfunction (Complex V activity, P = 0.02) in liver. In the prolonged phase, hepatic autophagy inactivation increased apoptosis (P = 0.01) and aggravated mitochondrial dysfunction (Complex V activity, P = 0.005) in liver. Autophagy deficiency did not affect mitochondrial DNA content (day 1 P = 0.98, day 3 P = 0.57). Autophagy deficiency time-dependently modulated several branches of the UPR in liver. On day 1, it decreased activation of the IRE1alpha-XBP1s (P = 0.003) and ATF6-CREB3L3 pathway (P = 0.003), coinciding with a diminished inflammatory response as shown by lower C-reactive protein gene expression (P = 0.006), but did not affect the p-eIF2alpha pathway (P = 0.26). At day 3, autophagy deficiency increased the activation of the p-eIF2alpha pathway (P = 0.03), but not the IRE1alpha-XBP1s (P = 0.37) or ATF6-CREB3L3 (P = 0.14) pathway.
Insufficient hepatic autophagy during critical illness aggravates liver damage, coinciding with more mitochondrial dysfunction and a time-dependent modulation of the UPR, hereby likely aggravating liver failure.
P353 Role of leptin and proprotein convertase subtilisin/kexin type 9 in modulating pulmonary inflammation in a murine model of early sepsis
M Khan1, D Dwivedi1, J Zhou1, A Prat2, NG Seidah2, PC Liaw1, AE Fox-Robichaud1
1McMaster University, Hamilton, Canada; 2Montreal Clinical Research Institute, Montreal, Canada
Obesity increases the risk of sepsis but how obesity shapes the immune responses to infection is unknown. Similar to patients, we previously demonstrated that Western diet fed obese mice have reduced lung inflammation during early sepsis. In this study we explore the potential mechanisms to explain this finding. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is a protein involved in cholesterol homeostasis that is implicated in sepsis survival. Leptin is a hormone produced by adipocytes that regulates energy homeostasis and is increased in obesity and sepsis. We hypothesized that either PCSK9 and/or leptin contributes to the obesity-associated lung protection in sepsis.
PCSK9 deficient, PCSK9 overexpressing and wild type mice on a C57/Bl6 background were fed either a high fat Western diet (WD) or a normal chow diet (NCD) for 15 weeks (n = 5/group). Sepsis was induced by cecal ligation and puncture (CLP). Tissues were harvested six hours post surgery. For the leptin studies mice were housed in static cages for 10-12 weeks. Mice were injected with recombinant leptin protein (1mg/kg)) one hour prior to CLP, then re-anesthetized and tissues collected at 6 hours. All mice were resuscitated with 2ml of lactated Ringers SQ pre surgery, and 1ml IV post surgery. Lung injury was assessed by myeloperoxidase (MPO in U/mg of tissue) assay of lung tissues and histopathology scores. Data are expressed as mean ± SEM and analyzed using ANOVA or t-test.
Septic PCSK9 over expressing mice fed NCD had greater lung MPO levels (46.5 ± 4.5) compared to PCSK9 deficient mice (31.1 ± 1.7) on NCD (p < 0.01). In mice fed the WD for 15 wks the protection from the loss of PCSK9 was no longer present, however the injury was reduced. Septic PCSK9 deficient (14.4 ± 1.4), wildtype (17.6 ± 0.9) and overexpressing (17.9 ± 1.0) mice on WD had no significant differences in lung MPO levels. This correlated with histopathology scores for PCSK9 deficient (0.7 ± 0.2), wildtype (1.1 ± 0.2) and PCSK9 overexpressing (1.3 ± 0.7) septic mice. We found that leptin treated septic mice had lower lung MPO (32.6 ± 1.6) levels compared to saline treated septic mice (46.6 ± 3.5) (p < 0.001). Sham operated mice had significantly lower MPO levels (12.7 ± 1.7 for leptin and 11.8 ± 1.2 for saline) compared to septic counterparts.
Our data suggests that both lack of PCSK9 and increases in leptin contribute to the lung protection in early sepsis. However, when exposed to a WD the potential benefits of PCSK9 deficiency to further reduce lung injury are no longer evident. These findings have implications for potential therapeutic strategies to reduce sepsis-induced lung injury.
P354 The role of oxygen delivery on plasma lactate and organ failure in experimental septic shock
M Von Seth, P Skorup, L Hillered, A Larsson, J Sjölin, M Lipcsey
Uppsala University, Uppsala, Sweden
The concept resuscitation of patients with septic shock, aiming at normalization of oxygen delivery (DO2), to limit tissue dysoxia and organ failure has not been confirmed in recent trials. Elevated plasma lactate in septic shock is considered as a key marker of inadequate DO2. We hypothesized that, apart from severely decreased levels, DO2 is not associated to plasma lactate in a model of septic shock.
We investigated the effects of circulatory shock and inflammation on plasma lactate in a retrospective analysis of 105 anesthetized endotoxemic (N = 61) or bacteremic (N = 44) piglets in shock. Tumor Necrosis Factor alpha (TNF-α) and Interleukin-6 (IL-6) were measured hourly during 6 hours (h) of shock. Muscle metabolism was monitored by microdialysis. The animals were stratified per degree of shock by DO2. The primary analysis was the breakpoint of insufficient DO2 to yield an elevated plasma lactate. ANOVA and regression models were used.
All animals developed macrocirculatory shock, elevated plasma and muscle lactate levels, elevated levels of cytokines in plasma, as well as renal and pulmonary failure. At 3 h, DO2 was 289 ± 68 mL x min-1 x m-2 (mean ± SD) and plasma lactate levels were 2.7 (2.0-3.6) mmol x L-1 (median(IQR)). Mixed venous saturation (SvO2) decreased and oxygen extraction increased linearly with DO2 (p > 0.001). Oxygen consumption (VO2) was not DO2 dependent.
Plasma lactate increased at DO2 < 250 mL x min-1 x m-2 (p < 0.001). Urinary output decreased at DO2 < 250 mL x min-1 x m-2 (p < 0.01), but static lung compliance was not DO2-dependent. Muscle glucose, lactate and pyruvate, urea and glutamate were not DO2-dependent. Muscle glycerol was DO2-dependent without breakpoint.
Plasma lactate correlated to Mean Arterial Blood Pressure (MAP), DO2 and peak IL-6, but not Systemic Vascular Resistance Index (SVRI) and peak TNF-α.Urinary output correlated to DO2 and MAP. Static lung compliance did not correlate to any parameters above.
Over time, muscle pyruvate increased and muscle glycerol and glucose decreased but no changes in muscle lactate and glutamate were seen. Muscle pyruvate correlated to MAP. Muscle glycerol correlated to MAP and to TNF-α.
In porcine experimental sepsis, elevated plasma lactate was only associated with very low DO2 while oxygen consumption was unaffected by low DO2 despite development of organ failure. Tissue metabolism was associated with both inflammatory and circulatory changes. Our findings suggest that the current concepts of resuscitation focusing on restoration of oxygen delivery must be combined with measures to limit the inflammatory response.
P355 The lung is not a significant source of lactate in a pig model of sepsis
A Otterbeck, K Hanslin, M Lipcsey, A Larsson, M Von Seth
Uppsala Universitet, Uppsala, Sweden
We used a porcine sepsis model to investigate pulmonary hypoxia as an explanation for lactate elevation in sepsis. We measured the pulmonary lactate production and shunt fraction during bacteremia. Sepsis is a condition characterized by severe organ failure as a result of a dysregulated response to infection. Central in many pathophysiological theories is the decreased delivery or utilization of oxygen by tissues. Normal physiology dictates that hypoxia leads to lactate production, a prognostic marker in sepsis. Thus, hypoxia has been used as an explanation for both organ dysfunction and elevated plasma (p-)lactate in sepsis. However, new research has implied other mechanisms. Previous studies have reported increased pulmonary lactate production in sepsis , the lungs being a generally well-oxygenated organ. However, these studies have not measured pulmonary shunt fraction and hence cannot estimate if the entire lung is ventilated.
We used 13 anesthetized pigs where 9 were randomized to a sepsis group and 4 were randomized to a sham group. All pigs received a pulmonary artery catheter and an arterial line. Pigs in the sepsis group were infused with live Escherichia coli for 3 hours (h) and in the sham group with NaCl. Blood cultures were used to confirm bacteremia. Blood gases, blood tests and physiological parameters were collected hourly. Lactate production was calculated by the p-lactate gradient from pulmonary artery to systemic artery and cardiac index. Shunt fraction was estimated at 3 h after ventilation with 100% O2 for 5 minutes.
Sepsis occurred in all pigs in the sepsis group, according to the criteria from Sepsis-3, and in no pigs in the sham group (p = 0.03). Global oxygen delivery (DO2) remained equal in both groups. Arterial lactate was higher (p = 0.003) in the sepsis group after 1 hour with a median value of 2.3 mmol/L vs. 0.95 mmol/L. Negative and positive lactate production occurred over the lungs in both groups (Fig. 2). There was no difference in pulmonary lactate production or pulmonary shunt fraction between groups. Neither group had significant shunt formation.
In this study we found a high p-lactate in septic pigs despite a high DO2. In absence of pulmonary shunts, the lung was not a major source, nor a major scavenger, of plasma lactate.
P356 Association between inflammation, mitochondrial function and lactate clearance
T Correa1, J Pereira1, J Takala2, S Jakob2
1Hospital Israelita Albert Einstein, São Paulo, Brazil; 2Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Systemic lactate clearance (LaCl) higher than 10% during the first hours of sepsis resuscitation is associated with better outcomes, but the mechanisms are unclear. We aimed to investigate the relationship between lactate clearance, inflammatory response, and mitochondrial respiration.
Original data from two previously published studies were re-analyzed [1,2]. In cohort 1, pigs were randomized to be resuscitated for 48h starting 6, 12 and 24h, respectively, after fecal peritonitis induction (n = 8, each) . Hemodynamics, inflammatory parameters, and mitochondrial function were analyzed. In cohort 2, 16 pigs with fecal peritonitis were immediately resuscitated for 24h . Regional lactate exchange was measured. Animals of both groups were categorized according to LaCl > =10% or <10% during 6h of resuscitation.
Overall mortality was 20% (4/20) for animals with LaCl > =10% and 60% (12/20) for animals with LaCl > =10% (p = 0.022). In cohort 1, systemic hemodynamics were similar in LaCl > =10% (n = 13) and LaCl < 10% (n = 11) groups. Plasma interleukin-6 levels were lower at study end in LaCl > =10% [45 (37-204) vs. 166 (128-310; median, IQR), p = 0.047]. Complex 1 state 3 [586 (386-688) vs. 353 (242-483), p = 0.026] and state 4 [157 (117-247) vs. 122 (89-151), p = 0.045], and Complex 2 state 3 [1156 (828-1401) vs. 761 (664-932), p = 0.041] and state 4 [376 (281-451) vs. 269 (225-326), p = 0.032] isolated brain but not hepatic, myocardial or skeletal muscle mitochondrial respiration were higher at study end in LaCl > =10% compared to LaCl < 10%. In cohort 2, mesenteric, total hepatic and renal blood flows were higher at study end in LaCl > =10% (n = 7) vs. LaCl < 10% group (n = 9), despite similar cardiac output. Hepatic lactate influx and uptake were approximately 1.5 and 3 times, respectively, higher in LaCl > =10% vs. LaCl < 10% (p = 0.066, both).
Systemic lactate clearance > =10% vs. <10% during early resuscitation after abdominal sepsis was associated with lower plasma interleukin-6, and higher brain mitochondrial respiration. Blood flow redistribution to abdominal organs in animals with high systemic lactate clearance increases the potential to deliver and extract lactate.
1. Correa TD et al. Effect of treatment delay on disease severity and need for resuscitation in porcine fecal peritonitis. Crit Care Med 40:2841–9, 2012.
2. Brandt S et al. Effect of fluid resuscitation on mortality and organ function in experimental sepsis models. Crit Care 13:R186, 2009.
P357 Dynamics of endotoxin, interleukin-6 and organ dysfunction after treatment with antibiotics in an E.coli porcine intensive care sepsis model
P Skorup1, L Maudsdotter2, E Tano1, M Lipcsey3, M Castegren1, A Larsson1, J Sjölin1
1Dept. of Medical Sciences, Uppsala, Sweden; 2Dept. of Molecular Biosciences, Stockholm, Sweden; 3Dept. of Surgical Sciences, Uppsala, Sweden
Endotoxin released during Gram-negative bacterial infections induces the production of pro-inflammatory cytokines and may accentuate the development of septic shock . Gram-negative bacteria exposed to â-lactam antibiotics in vitro release endotoxin but in a minor extent when the â-lactam antibiotic is combined with an aminoglycoside . The primary purpose of the study was to investigate the dynamics in endotoxin and interleukin-6 (IL-6) concentration as well as leukocyte activation and subsequent organ dysfunction in a large animal intensive care sepsis model in order to explore the relevance of antibiotic-induced endotoxin liberation and inflammatory response in vivo. Whether the addition of an aminoglycoside to a â-lactam antibiotic results in a reduced endotoxin release and systemic inflammation constituted a secondary aim.
A prospective placebo-controlled study was conducted on anesthetized pigs in an intensive care setting. All pigs were administered Escherichia coli as a 3h intravenous infusion. At 2h the animals were subjected to antibiotic treatment (n = 18) receiving either cefuroxime alone (n = 9) or the combination of cefuroxime and tobramycin (n = 9), whereas controls received saline (n = 18). During 4h after administration of antibiotics/saline, plasma endotoxin, IL-6, leukocytes and organ dysfunction variables were recorded hourly and differences to the values before treatment were calculated.
All animals developed sepsis. Antibiotic-treated animals demonstrated a higher IL-6 response (p < 0.001), stronger leukocyte activation (p < 0.001) and more pronounced deterioration in pulmonary static compliance (p < 0.01) over time in comparison with controls. Animals treated with the combination demonstrated only a trend towards less inflammation in comparison with animals treated with cefuroxime alone. In plasma no differences in endotoxin concentration were observed between the groups.
Treatment with antibiotics elicits an inflammatory IL-6 response which is associated with leukocyte activation and pulmonary organ dysfunction, whereas no observable differences were seen in plasma endotoxin concentration. The reduction in cefuroxime-induced endotoxin release after the addition of an aminoglycoside in vitro could not be reproduced in vivo.
1. Bozza FA et al.: Crit Care 2007; 11: 1.
2. Goscinsky G et al.: Scand J Infect Dis 2003; 35: 40–6
P358 Persisitent shift of th1 to th2 in one week after diagnosis of community-acquired severe sepsis predicts mortality
M Xue, JY Xu, L Liu, YZ Huang, FM Guo, Y Yang, HB Qiu
Southeast University, Nanjing, China
Recent studies have revealed that inflammation mediated by CD4+ T cells may contribute to the pathogenesis of sepsis. The role of the Th(T helper)1/Th2 balance in sepsis remains largely unknown. The aim of this study was to investigate the th2/th1 pattern and its impact on disease severity and outcomes in patients with new onset community-acquired severe sepsis.
This was a prospective observational study. Patients with community-acquired severe sepsis admitted to ICU within 24 hours were included. Blood sample was collected on day of admission(Day0, D0), 3rd Day (D3) and 7th Day (D7) after admission. Th2 and Th1 in lymphocyte were tested by flow cytometry. The increase of th2/th1 (>0.22) indicated immunosuppression. According to the change of th2/th1, patients were divided into 3 groups: immunosuppression recovered in early stage (th2/th1 began to decrease on D3, Group 1), immunosuppression recovered in late stage (th2/th1 began to decrease on D7, Group 2), immunosuppression worsened (th2/th1 kept increasing in a week, Group 3). The organ dysfunction, hospital-acquired infection(HAI) and 28-day prognosis was recorded. All patients or their legal representatives provided written informed consent. The study is registered with ClinicalTrials.gov, NCT 02883218.
Seventy-four patients were eligible for study during Sept 18, 2014 to Sept 30, 2016. There were 34 cases in Group 1, 19 cases in Group 2, and 21 cases in Group 3. Baseline characteristics(age, sex, source of bacteremia, presence of comorbidities) of the population in different groups were similar.
(1) Compared with Group1(11.8%), Group3(52.4%) showed a significantly higher 28-day mortality(P = 0.001), while group 2 showed a higher 28-day mortality of 31.6% with no significant difference (Fig. 3).
(2) There were no significant differences in terms of incidence of HAI and organ dysfunction among groups.
(3) The areas under the receiver operating characteristic (AUC) curves of value of th2/th1 on D7 was of great value(0.875)(Fig. 4). Using a th2/th1 on day7 cutoff value of >2.74 to determine 28-day mortality, the sensitivity was 76.2% with 96.1% specificity.
Persisitent shift of th1 to th2 in one week after diagnosis of community-acquired severe sepsis may be a predictor for immunosuppression. Patients with persistently increasing th2/th1 have poor outcome.
 Leentjens J, Kox M, Rebecca M, et al. Reversal of immunoparalysis in humans in vivo. Am J Respir Crit Care Med. 2012, 186: 838–845.
 Monneret G, Venet F, Pachot A et al. Monitoring immune dysfunctions in the septic patient: a new skin for the old ceremony. Mol Med. 2008, 14: 64–78.
P359 Genetic variants of intron region of aquaporin AQP5 gene and development of pulmonary edema in lung infection complicated by septic shock
A Kuzovlev, V Moroz, A Goloubev, A Myazin, A Chumachenko, V Pisarev
V.A. Negovsky Research Institute of General Reanimatology, Moscow, Russia
Product of AQP5 gene belongs to a family of aquaporins (AQPs), membrane proteins, responsible for the selective transmembrane transport of water. However, the value of polymorphic variants AQP5 in the development and progression of pul_monary edema in severe lung infection was studied so far. The aim of the investigation was to determine the value of genetic variants of a single nucleotide polymorphic site rs3736309 of intron 3 of aquaporin_5 (AQP5) gene in the course of critical illness in patients with documented pulmonary infection.
Patients with critical illness admitted to the intensive care units were examined during the course of treatment (n = 86, age 27 to 82 years, mean age 53.20 ± 14.34 years). Main diagnosis included malignancies (15%), peritonitis (16%) and necrotizing pancreatitis (37%). Patients developed nosocomi_al pneumonia (55%), acute respiratory distress syndrome (ARDS) (54%), septic shock (48%), ARDS combined with septic shock (33%). DNA genotyping was carried out using tetra_primer polymerase chain reaction (PCR). Statistical processing was performed using GraphPad InStat program (GraphPad, USA).
The distribution of frequencies of genotypes AA, GA and GG (AQP5, rs3736309) in cohort of patients corresponded to Hardy_Weinberg equilibrium (P = 0.923) and was similar to frequencies of the alleles determined in healthy Caucasian individuals (literature data) (P > 0.05). In a subgroup of patients with septic shock and AQP5 AA (rs3736309) genotype the lower EVLWI values were found compared to patients with geno_types GG and GA with septic shock in spite of the same approach to treatment. Genetic variant AQP5 G+ (rs3736309) contributed to the development of pulmonary edema resistant to treatment (odds ratio, OR = 6,75; P = 0.032). Only the subgroup of patients with septic shock and geno_type G + (but not all patients or the subgroup of patients without septic shock of the same genotype) were char_acterized by significantly elevated levels of surfactant protein SP_D in plasma compared to patients of genotype AQP5 AA with septic shock (P < 0.05).
In septic shock, the presence of homozygous variant allele A (AA) of AQP5 rs3736309 is a favor_able factor for patients developing the pulmonary edema. The presence of allele AQP5 G (rs3736309) is a risk fac_tor for developing severe pulmonary edema and unfavorable prognosis in spite of treatment.
P361 Altered T cell repertoire diversity and increased PD-1 expression predict mortality in patients with septic shock
N Takeyama, M Tsuda, H Kanou, R Aoki, Y Kajita, M Hashiba, T Terashima, A Tomino
Aichi Medical University, Aichi, Japan
Sepsis causes impairment of innate and adaptive immunity by multiple mechanisms, including depletion of immune effector cells and T cell exhaustion. Although lymphocyte dysfunction is associated with increased mortality and potential reactivation of latent viral infection in patients with septic shock, the relation between viral reactivation and lymphocyte dysfunction is obscure. The objectives of this study were 1) to determine the relation of lymphocyte dysfunction to viral reactivation and mortality, and 2) to evaluate recovery of lymphocyte function during septic shock, including T cell receptor (TCR) diversity and the expression of programmed death 1 (PD-1).
In 18 patients with septic shock and latent cytomegalovirus infection, serial blood samples were obtained on days 1, 3, and 7 after the onset of shock, and immune cell subsets and receptor expression were characterized by flow cytometry. TCR diversity of peripheral blood mononuclear cells was analyzed by Multi-N-plex PCR, and cytomegalovirus DNA was quantified using a real-time PCR.
Monocytes showed a decrease of TCR diversity and HLA-DR expression in the early stage of septic shock, while CD4+ T cells displayed an increase of PD-1 expression. Normalization of TCR diversity and PD-1 expression was observed by day 7, except in patients who died. cytomegalovirus reactivation was detected in 3 of the 18 patients during the first week of their ICU stay and all 3 patients died.
These changes are consistent with the early stage of immune cell exhaustion and indicate the importance of normal lymphocyte function for recovery from septic shock. Ongoing lymphocyte dysfunction is associated with cytomegalovirus reactivation and dissemination, as well as with unfavorable outcomes.
P362 Vasopressin alone and with noradrenaline attenuates TNF-α production in an in-vitro model of monocyte priming and deactivation
R Davies, KP O´Dea, S Soni, JK Ward, DJ O´Callaghan, M Takata, AC Gordon
Imperial College, London, United Kingdom
Vasopressin is a safe and effective ‘catecholamine-sparing’ vasopressor in septic shock . It also has anti-inflammatory properties, including inhibition of endotoxin-induced inflammatory cytokine release from macrophages in-vitro . To further assess vasopressin’s anti-inflammatory effects in sepsis, we developed an in-vitro assay of monocyte priming and deactivation to model the pro- and anti-inflammatory responses, respectively.
Healthy volunteer CD14+ monocytes were cultured at 37°C for 20hrs with lipopolysaccharide (LPS, 100pg/ml) or IL-10 (10ng/ml), in combination with noradrenaline (5000pg/ml) and ‘high’ (300pmol/L) or ‘low’ (100pmol/L) dose vasopressin. Monocytes were analysed for HLA-DR and CD86 (T-cell co-stimulatory ligand) expression by flow cytometry, or stimulated with a ‘second-hit’ of LPS (10ng/ml) and TNF release measured by ELISA.
Pre-treatment of monocytes with LPS resulted in a primed phenotype of higher HLA-DR expression and TNF release on stimulation, whereas IL-10 reduced HLA-DR, CD86, and TNF release indicating a deactivated phenotype. Under normal and priming conditions, co-incubation with vasopressin alone or with noradrenaline significantly reduced TNF release (Fig. 5), but not HLA-DR/CD86 expression. In contrast, neither vasopressin nor noradrenaline affected the IL10-induced deactivated phenotype.
The vasopressin-mediated suppression of TNF release in normal or primed monocytes, but not in deactivated monocytes, suggests a selective immune-modulatory activity that may be beneficial in septic patients and warrants further investigation.
1. Gordon AC et al. JAMA.316:509–18,2016
2. Peng T-C et al. Tzu Chi Medical Journal.25:150–4,2013
P363 Relationship between lymphocyte subset expression and serum concentrations of pd-1/pd-l1 in sepsis – pilot study
J Wilson1, Y Zhao1, M Singer2, J Spencer1, M Shankar-Hari1
1King’s College London, London, United Kingdom; 2Bloomsbury Institute of Intensive Care Medicine, London, United Kingdom
Programmed death antigen (PD-1) and ligand (PD-L1) are inducible negative regulators on leukocyte surface. The PD-1/PD-L1 pathway contributes to lymphocyte exhaustion and immunosuppression in sepsis . A clinical trial is currently evaluating the safety of an anti-PD-L1 antibody in sepsis patients . However, serum levels and differences in PD-1/PD-L1 expression by B and T cell subsets are unknown and are likely to influence the efficacy of this intervention. We tested the hypothesis that surface PD-1/PD-L1 expression will differ in B and T cell subsets, and that serum PD-1/PD-L1 levels will be high in sepsis.
A prospective observational cohort study in 22 critically ill adult sepsis patients, excluding those with immune deficiency states, was done with ethics approval and informed consent. Blood was taken on ICU admission day and PBMCs isolated. Patients (11 survivors & 11 non-survivors) were compared with contemporaneously collected and analysed samples from 11 healthy controls. Cell surface staining was performed with antibodies to CD3, CD19 [BD Biosciences], CD4, CD27, PD-1, PD-L1 and PD-L2 [Biolegend], and live dead stain Amcyan [Invitrogen]. FACS analyses were performed on a FACScalibur flow cytometer [BD Biosciences] and using Tree Star FlowJo software. Serum PD-1 and PD-L1 in the same cohort were measured by ELISA [Proteintech]. Data was analysed using PRISM.
The percentages of B and CD4+ T cells expressing PD-1 and PD-L1 were significantly higher in survivors and non-survivors of sepsis compared to healthy controls. There were no significant differences between survivors and non-survivors in expression of PD-1 or PD-L1 by any lymphocyte subset. CD4 + CD27- memory T cells had significantly higher mean fluorescence intensity (MFI) and percentage positivity of PD-1 than CD4 + CD27+ T cells. The PD-1 MFI was significantly higher in CD19 + CD27+ memory B cells than CD19 + CD27- B cells. Serum PD-1 and PD-L1 concentrations were not different in sepsis patients compared to controls and values did not correlate with surface expression of PD-1 or PD-L1 by any lymphocyte subset in sepsis patients.
We show higher expression of PD-1 and PD-L1 by B cells and CD4+ T cells in sepsis compared to health, and higher expression of PD-1 by memory compared to naïve B cells and CD4+ T cells. Further research to identify patients likely to benefit from PD-1/PD-L1 blockade in sepsis is required.
1. Hotchkiss R et al. Nat Rev Imm; 13(12):862–74, 2013.
3. Singer M et al. JAMA; 315(8):801–10, 2016.
P364 Pcsk9 loss-of-function genotype is associated with better short and long-term outcomes in sepsis
K Roveran Genga1, C Lo1, M S. Cirstea1, K R. Walley1, J A. Russell1, A Linder2, J H. Boyd1
1Center for Heart Lung Innovation - University of British Columbia (UBC), Vancouver, Canada; 2Lund University, Lund, Sweden
Reduced activity of proprotein convertase subtilisin/kexin type 9 (PCSK9), by increasing the density of low density lipoprotein (LDL) receptors on hepatic cells, may decrease the systemic inflammatory response to sepsis due to increased clearance of pathogen lipids incorporated into LDL . The purpose of this study was to determine the relationship between PCSK9 loss-of-function (LOF) variants and the risk of short and long-term death and/or hospital readmission(s) within a year following an episode of sepsis, in two distinct cohorts.
This was a retrospective observational study involving two cohorts from St. Paul’s Hospital in Vancouver, Canada: Cohort 1 was composed by 189 patients with septic shock admitted to intensive care unit between July 2000 and January 2004 and who survived at least 60 days post- hospitalization; Cohort 2 included 185 patients admitted to the Emergency Department from January 2011 to July 2013, with clinical diagnosis of sepsis. R46L, A53V, and I474V PCSK9 missense LOF SNPs were genotyped in all patients, who were classified in 3 groups: WT, 1 LOF, and 2 or more LOF according to the number of LOF alleles.
Cohort 1: Time to event curves for 5-year mortality showed a trend to statistically lower probability of death within 5 years in patients with PCSK9 LOF (overall p = 0.062) and the presence of 1 PCSK9 LOF allele (Cox model) was independently associated with decreased hazard-ratio for 5-year mortality (0.578, 95% CI = 0.36-0.93, p = 0.024).
Cohort 2: Patients from the 2 or more LOF group had lower probability of death within 90 days in comparison to WT (p = 0.010) or 1 LOF patients (p = 0.028), and the presence of 1 PCSK9 LOF allele (Cox model) was independently associated with decreased HR for 90-day mortality (0.46, 95% CI 0.23-0.92, p = 0.030). Patients from the 2 or more PCSK9 LOF group also had lower probability of death or infection related readmissions when compared to WT (p = 0.015) or 1 LOF allele (p = 0.002), and the presence of 2 or more PCSK9 LOF alleles had the lowest adjusted HR for this outcome (HR = 0.32, 95% C.I. 0.11-0.92, p = 0.035).
PCSK9 LOF genotype is associated with decreased risk of 5-year and 90-day mortality, and all-cause 1-year death or readmissions due to infection after an episode of sepsis.
1. Walley KR et al.: Science translational medicine Sci Transl Med. 6(258):258ra143, 2014
P365 Monocyte surface marker expression profile and cytokine secretion of critically ill patients with pseudomonas aeruginosa induced sepsis
A Sedlag1, C Riedel1, M Georgieff2, E Barth2, H Bracht2, A Essig2, D Henne-Bruns2, F Gebhard2, K Orend2, M Halatsch2, M Weiss2
1University, Ulm, Germany; 2University Hospital Medical School, Ulm, Germany
Some critically ill patients are at high risk of severe sepsis due to infections with Pseudomonas aeruginosa (PSA) in the lung or abdomen, which is difficult to treat. The present study was performed to find out whether these critically ill patients on a surgical intensive care unit with sepsis due to PSA have a characteristic monocyte surface receptor expression and cytokine secretion patterns.
The surface markers CD163 (hemoglobin scavenger receptor; clearance of hemoglobin, adhesion to endothelial cells, tolerance induction, tissue regeneration; soluble form: antiinflammation), CD206 (mannose receptor for mannose on surface on microorganisms), intracellular levels of IFN-γ, CXCR1 (IL-8α chemokine receptor) and CXCR2 (IL-8β chemokine receptor) of monocytes of critically ill patients with PSA sepsis and of healthy controls were analyzed by flow cytometry. Furthermore, the IL-8 secretion levels in vivo and ex vivo after LPS stimulation were determined by ELISA.
20 surgical patients with severe sepsis / septic shock with underlying PSA infections and of 22 healthy controls were monitored. The monocytes of the patients showed differences in the IL-8 secretion level. In line with high IL-8 or low IL-8 secretion in serum (965 ± 139 pg/ml vs. 232 ± 15 pg/ml) as well as in culture after LPS stimulation (2838 ± 259 pg/ml vs. 1097 ± 356 pg/ml), the expression of surface markers IFN-γ, CXCR1, CXCR2 and CD163 was high or low, respectively, however, always above those of the healthy control group (p < 0.05). CD206, only, showed the opposite behavior in that CD206 was highly expressed (3657 ± 279 MFI) on IL-8 low cells, whereas a low expression (17 ± 6 MFI) could be observed on IL-8 high cells (p < 0.001). The IL-8 low group had markedly higher severity of disease scores (SAPSII 34 ± 8) than the IL-8 high group (SAPSII 17 ± 6), and worse outcome (p < 0.001).
Different patterns of monocyte surface pattern expressions are associated with low or high IL-8 secretion of monocytes in patients with PSA sepsis. Low IL-8 expression and the respective surface pattern on monocytes may be associated with worse outcome.
P366 Identification of a distinct metabolomic profile in acute influenza infection
M Chase1, E Freinkman2, A Uber1, X Liu1, MN Cocchi1, MW Donnino1
1Beth Israel Deaconess Medical Center, Boston, MA, United States; 2Whitehead Institute, Cambridge, MA, United States
The goal of this investigation is to characterize the effect of acute influenza infection on the host metabolome. Metabolomics is an emerging field of research studying small molecules or metabolites providing a profile of the physiologic status of an organism at a point in time. The human metablomic response to acute influenza infection is not well-characterized. We hypothesized that acute influenza infection will induce a distinct metabolic response in the host which may enable the identification of host mediators in influenza pathogenesis.
We are conducting a randomized clinical trial administering atorvastatin or placebo to patients with acute influenza infection. As an exploratory aim, we assessed the metabolomic profile of enrolled patients at baseline, prior to study drug administration, compared to healthy controls. T-tests were used to compare 117 metabolites. Raw data were entered into MetaboAnalyst statistical software for analysis. We report findings based on Partial Least Squares-Discriminant Analysis (PLS-DA) which uses multivariate regression techniques to predict class membership based on original variables.
We performed metabolomic analysis on serum samples of 49 statin-naïve patients with acute influenza and 25 healthy controls. We found 17 individual metabolites that were significantly different between groups at a threshold of p = 0.05. PLS-DA score plot demonstrated a distinct difference between influenza subjects and controls (Fig. 6) and PLS-DA model validation by permutation tests was highly significant (p < 5e-04). The most significant discriminating metabolites between influenza patients and controls were phosphocholine, phosphoethanolamine, nicotinamide, taurine, ADP, tryptophan, threonine, proline, citrulline (lower in flu samples) and kynurenine, acetoacetate, 3-hydroxybutyrate, hypoxanthine (higher in flu samples). Each of these metabolites had a VIP score of >1.4
P367 Von Willebrand factor and ADAMTS-13 influence the outcome of s. aureus bacteremia
M Peetermans1, L Liesenborghs2, J Claes2, T Vanassche2, M Hoylaerts2, M Jacquemin2, K Vanhoorelbeke2, S De Meyer2, P Verhamme1
1UZ Leuven, Leuven, Belgium; 2KU Leuven, Leuven, Belgium
The size and functionality of the multimeric von Willebrand factor (VWF) molecule is regulated by its cleaving protease ADAMTS-13. While VWF and ADAMTS-13 levels correlate with disease course and outcome in the heterogenous population of septic patients, animal models have been inconclusive and mainly focused on gram-negative abdominal sepsis. It is unknown if modulation of the VWF/ADAMTS-13 balance can modulate the outcome of [i]S. aureus[/i] sepsis.
We aimed to study the role of VWF and ADAMTS-13 in [i]S. aureus[/i] sepsis, using patient data and an animal model.
In patients with [i]S. aureus[/i] bloodstream infection, high VWF levels correlated with inflammatory parameters and inversely with kidney function. Low ADAMTS-13 levels were associated with disease severity and DIC parameters.
In a severe sepsis model, mice deficient in VWF showed improved survival, compared to wildtype mice. In contrast, [i]Adamts13-/-[/i] mice had increased mortality. Immediate clearance of bacterial load in blood was better in VWF deficient mice. The differences in mortality for the studied genotypes were associated with differential loads of organ microthrombi in liver and kidneys. Further experiments will study if administration of ADAMTS-13 can alleviate the course of [i]S. aureus[/i] sepsis.
In conclusion, this is the first study that consistently shows the relation of VWF, ADAMTS-13 and their ratio to disease severity in patients and mice with [i]S. aureus[/i] sepsis. Not only is the balance of VWF and its cleaving protease implicated in primary adhesion and bacterial retention, but VWF/ADAMTS-13 ratio also regulates the amount of organ microthrombi containing platelets, neutrophils and bacteria – and thus potentially end organ failure.
Targeting VWF multimers and/or the relative ADAMTS-13 deficiency that occurs in sepsis, should be explored as a potential new therapeutic target in [i]S. aureus[/i] endovascular infections.
P368 Admission levels of asymmetric and symmetric dimethylarginine predict long-term outcome in patients with community-acquired pneumonia
A Vögeli1, M Ottiger1, M Meier1, C Steuer1, L Bernasconi1, A Huber1, M Christ-Crain2, C Henzen3, C Hoess4, R Thomann5, W Zimmerli3, B Müller1, P Schütz1
1Kantonsspital Aarau, Aarau, Switzerland; 2University Hospital Basel, Basel, Switzerland; 3Kantonsspital Luzern, Lucerne, Switzerland; 4Kantonsspital Münsterlingen, Münsterlingen, Switzerland; 5Bürgerspital Solothurn, Solothurn, Switzerland
During infection, there is an activation of the L-arginine-nitric-oxide pathway, with a shift from nitric oxide synthesis to a degradation of L-arginine to its metabolites, asymmetric and symmetric dimethylarginine (ADMA and SDMA). We investigated the association of L-arginine, ADMA, and SDMA with adverse clinical outcomes in a well-defined cohort of patients with community-acquired pneumonia (CAP).
We measured L-arginine, ADMA, and SDMA in 268 CAP patients from a Swiss multicenter trial by mass spectrometry and used Cox regression models to investigate associations between blood marker levels and disease severity as well as mortality over a period of 6.1 years.
Six-year mortality was 44.8%. Admission levels of ADMA and SDMA (μ mol/L) were correlated with CAP severity as assessed by the pneumonia severity index (r = 0.32, p < 0.001 and r = 0.56, p < 0.001 for ADMA and SDMA, respectively) and higher in 6-year non-survivors versus survivors (median 0.62 vs. 0.48; p < 0.001 and 1.01 vs. 0.85; p < 0.001 for ADMA and SDMA, respectively). Both ADMA and SDMA were significantly associated with long-term mortality (hazard ratios [HR] 4.44 [95% confidence intervals (CI) 1.84 to 10.74]) and 2.81 [95%CI 1.45 to 5.48], respectively). No association of L-arginine with severity and outcome was found.
P369 Decreased functional protein c levels may be predictive of the severity of sepsis associated coagulopathy and DIC
D Hoppensteadt1, A Walborn1, M Rondina2, K Tsuruta3, J Fareed1
1Loyola University, Chicago, IL, United States; 2University of Utah School of Medicine, Eccles Institute of Human Genetics, Salt Lake City, UT, United States; 3Asahi Kasei Pharma America Corporation, Waltham, United Kingdom
Sepsis is a severe systemic inflammatory response to infection that manifests with widespread inflammation as well as endothelial and coagulation dysfunction that may lead to hypotension, organ failure, shock, and death. Disseminated intravascular coagulation (DIC) is a complication of sepsis involving systemic activation of the fibrinolytic and coagulation pathways that can lead to multi-organ dysfunction, thrombosis, and bleeding, with a two-fold increase in mortality. Several studies have reported that low levels of protein C predict outcome in patients with severe sepsis. Protein C helps to regulate coagulation by controlling the activation of factors Va and VIIIa. In addition, activated protein C has anti-inflammatory functions. The purpose of this study was to determine the functional protein C levels in this cohort of patients over the 8 day study period and to correlate protein C levels with survival.
De-identified serial plasma samples from patients diagnosed with sepsis-associated coagulopathy (n = 137) were obtained from the University of Utah under an IRB approved protocol. The citrated plasma samples were collected from adult patients in the ICU upon admission and ICU days 4 and 8. In addition, plasma samples from healthy volunteers (n = 50) were purchased from George King Biomedical (Overland, KS). P). Patients were assigned a DIC score based on the International Society of Thrombosis and Hemostasis (ISTH)criteria and categorized as having sepsis and no DIC, non-overt DIC and overt DIC. Plasma samples were analyzed for functional protein C levels using a clot-based method (Diagnostica Stago, Parsippany, NJ).
The functional protein C levels on day 0 and day 4 were decreased in the septic patients compared to normal controls (p < 0.0010). In addition, the functional protein C levels decreased with an increase in severity of DIC. On day 8, there was a decrease in the functional protein C levels in both the non-overt and overt DIC groups compared to normal and patients with sepsis and no DIC. There also was a significant decrease in functional protein C levels in survivors compared to non-survivors (p < 0.010).
These results underscore the importance of functional protein C levels in the regulation of hemostasis. Furthermore, these studies demonstrate that decreased functional protein C contributes to the pathogenesis of sepsis associated coagulopathy as evident by the observed relationship with the severity of sepsis and decreased protein C levels. Thus functional protein C levels may be a useful prognostic marker to risk stratify patients with sepsis and DIC.
P370 Cholesterol is a marker of multiple organ dysfunction syndromes after abdominal surgeries.
Mogilev Regional Hospital, Mogilev, Belarus
According to the third international consensus sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. The aim of the study was to investigate the possibility of using additional laboratory marker cholesterol for early detection of multiple organ dysfunction syndromes (MODS) after abdominal surgeries.
After approval the ethics committee of the Mogilev Regional Hospital in a prospective observational study included 58 patients aged 18 to 85 years. All patients underwent laparotomy abdominal surgeries after which hospitalized in the intensive care unit. In R group (n = 30) of patients in the postoperative period was followed by the development of MODS, in the C group (n = 28) - patients without MODS. Determination of cholesterol produced daily by AU 680 biochemistry analyzer.
Patients on the R group marked decrease in the level of cholesterol on the 4th day after surgery with 158.7 (96.8; 189.6) mg / dL to 127.7 (112.2; 174.1) mg / dL (Wilcoxon test, p = 0.0035). In group C was no significant differences in cholesterol levels. In R group value of cholesterol on 4th day was significantly higher in patients (n = 17) with recovery 147.1 (112.2; 170.3) mg / dL, than in patients (n = 13) with a fatal outcome 116.1 (100.6; 127.7) mg / dL (Mann-Whitney U test, p = 0.034). In the surviving patients reduced cholesterol level normalization was observed after 14 days after the operation.
We performed ROC-analysis to determine the diagnostic significance of cholesterol as a marker MODS. The area under the curve was 0.726 (p <0.001) 95% confidence interval from 0.684 to 0.769, sensitivity 73.6%, specificity 63.8%. The optimal threshold level of cholesterol as a predictor of MODS was determined of 130.0 mg / dL.
Determining the level of cholesterol, together with an assessment of clinical symptoms and blood formula, will provide early diagnosis of MODS after abdominal surgeries.
P371 Relationship between white blood cell count and sepsis-related biomarkers in critically ill patients
T Ikeda, S Ono, T Ueno, S Suda, T Nagura
Hachiouji medical center, Tokyo medical university, Tokyo, Japan
Antibiotic therapy is a very important treatment for critically ill patients, but long-term administration can lead to antimicrobial resistance. Procalcitonin (PCT) has been used as a biomarker to monitor the effectiveness of antibiotic therapy with the aim of shortening the administration period. This study aimed to clarify the relationship of WBC counts to sepsis-related biomarkers (procalcitonin [PCT], endotoxin activity assay [EAA], interleukin-6 [IL-6], and presepsin) and 28-day mortality rate in critically ill patients.
We studied 422 patients (L-group with WBC counts <4000: 79 patients; H-group with WBC counts >12,000: 343 patients). Blood biochemistry and PCT, EAA, IL-6, and presepsin were measured immediately after ICU admission. Results were expressed as the mean ± SD (median). The Mann-Whitney U-test and chi-square test or Fisher’s exact test were used for statistical analysis. A p-value of <0.05 was considered to indicate a statistically significant difference.
Regarding background factors, the APACHE2 scores in the L-group and H-group were 24.9 ± 9.2 (23.5) and 22.4 ± 9.1 (23.0), and the SOFA scores were 9.3 ± 3.9 (9) and 12.9 ± 3.4 (8), respectively. These values showed no significant differences between groups. PCT levels in the L-group and H-group were 65 ± 96 (25) and 20 ± 51 (3.2) respectively; EAA levels in the L-group and H-group were 0.59 ± 0.26 (0.62) and 0.36 ± 0.22 (0.32), respectively. IL-6 levels in the L-group and H-group were 61,728 ± 10,8417 (15,150) and 2440 ± 3422 (217), respectively. All of these values in the L-group tended to be higher than in the H-group. On the other hand, presepsin levels in the L-group and H-group were 1277 ± 943 (882) and 2440 ± 422 (1210), respectively. The 28-day mortality rate in the L-group was 34%, and 14.7% in the H-group. There was a significant difference between groups (p < 0.05).
In critically ill patients who entered the ICU, most sepsis-related biomarkers (PCT, EAA, IL-6) tended to be higher in the low leukocyte count (WBC < 4000) group, but only presepsin tended to be higher in the high WBC (>12,000) group. Further study to explain this difference is necessary.
P372 Neutrophil-lymphocyte ratio and mortality during critical illness
E Damiani, R Domizi, C Scorcella, S Tondi, S Pierantozzi, S Ciucani, N Mininno, E Adrario, P Pelaia, A Donati
Università Politecnica delle Marche, Ancona, Italy
Immunologic alterations are common during critical illness and may determine outcome. We evaluated whether lymphopenia (lymphocyte count <1000*106/mmc) or a higher neutrophil-lymphocyte ratio (NLR, as a marker of inflammation) were associated with mortality in critically ill patients.
Prospective observational study on 221 consecutive adult patients admitted to our 14-bed Intensive Care Unit (ICU). Neutrophil and lymphocyte counts were recorded every day. Receiver operating characteristics (ROC) curves and binary logistic regression analysis were used to test the association between lymphopenia/NLR and ICU-mortality.
83% of patients showed lymphopenia at least once in the ICU stay. The mean lymphocyte count was a weak discriminant of ICU-mortality (area under the ROC curve: 0.63 [95% confidence interval 0.52-0.74]). A mean NLR [>=] 12 was able to discriminate Non-survivors with a sensitivity of 64% and specificity of 71% (ROC: 0.71 [0.61-0.80], Fig. 9). A mean NLR [>=] 12 was associated with higher mortality independently of age, presence of infection, days of mechanical ventilation and the Simplified Acute Physiology Score (adjusted odds ratio: 3.597 [1.760-7.354]).
P373 Leukocyte activity assessment using magnetic levitation in septic patients
M Schou Andersen1, S Lu1, G Lopez1, AT Lassen2, I Ghiran1, NI Shapiro1
1Beth Israel Deaconess Medical Center, Boston, MA, United States; 2Odense University Hospital, Odense, Denmark
In sepsis, chemotactic factors induce swelling and activation of leukocytes. We have invented a novel portable bedside device based on the principles of magnetic levitation (two opposing magnets with a capillary tube in between that suspend cells) to image and quantify morphological properties of circulating leukocytes using whole blood. The device separates blood cells based on their mass and magnetic properties. Our aim was to determine whether magnetic levitation technique, by measuring leukocyte size and morphology parameters can accurately identify Emergency Department(ED) patients with sepsis.
Single-center, prospective, observational cohort study of a convenience sample of adult (>17y) patients from a 56.000 visit ED or affiliated out-patient lab between 3/2016-11/2016. Inclusion criteria: Sepsis: patients admitted to the hospital with suspected or confirmed infection. Non-infected Controls: ED or outpatient clinic patients without infection or acute illness. Procedures: Half a microliter of whole blood collected in EDTA tube, mixed with a paramagnetic gadolinium solution, transferred to a capillary tube, and placed between magnets for imaging and data analysis. Primary analysis: comparison of sepsis patients vs non-septic controls. Covariates of interest: leukocyte area, length, width, roundness, standard distribution(SD) of levitation height (measure of mass/charge dispersion). Means reported with t-test comparisons and calculation of area under the curve for assessment of diagnostic accuracy.
We enrolled 41 non-infected controls and 21 sepsis patients: sepsis(6), severe sepsis(9) and septic shock(6). Our analyses identified a significant increase in the size of the circulating leukocytes in sepsis patients versus controls, as seen by the following morphology parameters: mean cell area, 570 pixels (SD) (±115) vs 411 (±46), p < 0.0001 with AUC = 0.89(0.80-0.99); cell length, 30 pixels (±2.5) vs 25 (±1.9), p < 0.0001, AUC = 0.89(0.81-0.98); and cell width, 27 (±2.4) vs 23 (±1.5), p < 0.0001, AUC = 0.93(0.86-1.00). Cell roundness was 2.2 (±1.1) vs 2.2 (±1.2), p = 0.9, AUC = 0.55(0.40-0.71). For mass:charge, levitation height SD was 71 (±26) vs 47 (±16), p = 0.0012, AUC = 0.80(0.67;0.93).
Septic patients had increased area, length, and width with strong diagnostic accuracy. Sepsis patients had leukocytes with a pattern of more variable mass and magnetic properties. Cell roundness was less promising. Trends towards these differences were associated with increased severity. This bedside technique shows promise as a novel diagnostic test for infection.
P374 Intensive care patients undergoing tracheostomy have different patterns of cytokine and biomarker response
U Trahtemberg1, S Sviri1, M Beil2, Z Agur3, P Van Heerden1
1Hadassah University Hospital, Jerusalem, Israel; 2Marienhaus-Kliniken, Saarlouis, Germany; 3IMBM, Bene Ataroth, Israel
Bedside tracheostomies are standardized, repeated procedures performed on relatively stable patients. The effects of tracheostomies at the biochemical level have not been studied before.
5 blood samples were obtained from patients undergoing bedside tracheostomies at t = 0, 4, 8, 12 and 24 hrs. Vital signs and clinical lab measures were also recorded. The blood samples were assayed for analytes shown in Fig. 10.
We report results for 23 patients from this ongoing study. Parametric and nonparametric tests showed few statistically significant changes between the time points. Clearly discernible patterns of response were observed, which were different between patients. Using a self-organizing map clustering algorithm, we were able to cluster the responses over time, for every analyte eg GCSF showed 3 possible patterns of response: peak at t = 2 and then a steady decrease (4 pts); peak at t = 2 and then a plateau starting at t = 3 (12 pts); and peak at t = 2 with an increase at t = 4 (5 pts; 2 pts were excluded by the algorithm). The other cytokines showed between 3 to 5 clusters of response patterns each.
P375 The h3 haplotype of the EPCR gene determines high sEPCR levels in critically-ill patients
E Jahaj1, A Vassiliou1, Z Mastora1, SE Orfanos2, A Kotanidou1
1Medical School of Athens University, Evangelismos, Athens, Greece; 2Medical School of Athens University, “Attikon” Hospital, Athens, Greece
The endothelial protein C receptor (EPCR) is a protein that regulates the protein C anticoagulant and anti-inflammatory pathways. A soluble form of EPCR (sEPCR) circulates in plasma and inhibits activated protein C (APC) activities. The clinical impact of sEPCR and its involvement in the septic process is under investigation. This study investigated possible association of EPCR haplotypes with sEPCR levels in critically-ill patients with suspected infection.
Two polymorphisms in the EPCR gene were previously genotyped in 239 Caucasian critically-ill patients, hospitalized in the intensive care unit (ICU) of “Evangelismos” Hospital, Athens, Greece. The old [1-2] and new  sepsis definitions were used to divide patients in groups. Patients were further divided according to their genotype. Plasma sEPCR levels were measured using a dedicated ELISA assay in all patients at the time of admission to the intensive care unit (ICU).
Patients were categorized using both old and new sepsis definitions. With the old definitions patients were divided in two groups: severe sepsis/septic shock-positive (SS/SS + ve) and severe sepsis/septic shock-negative (SS/SS-ve). sEPCR levels were slightly higher in the SS/SS-ve group (p < 0.05). The patients were also divided according to their qSOFA score. In the three groups of patients, sEPCR levels were comparable (p > 0.05). However, when patients were divided according strictly to their genotype, plasma levels of sEPCR differed between genotypes (p < 0.0001) and between H3 and non-H3 carriers (p < 0.0001), with higher sEPCR levels in the H3 carriers.
Frequencies of SNPs determining EPCR haplotypes were in concordance with Caucasian frequencies. Critically-ill patients carrying at least one H3 allele had significantly higher levels of sEPCR than patients with no H3 alleles. Using both classification systems, sEPCR levels were not associated with sepsis severity.
1. ACCP/SCCM Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Critical care medicine 1992, 20(6):864–874.
2. Levy MM et al.: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive care medicine 2003, 29(4):530–538.
3. Singer M et al.: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). Jama 2016, 315(8):801–810.
P376 The vasopressin surrogate marker copeptin reflects stress and predicts adverse clinical outcomes in unselected emergency patients: results of a multinational prospective cohort study
Y Wirz1, R Sager1, D Amin2, A Amin2, S Haubitz1, P Hausfater3, A Huber1, A Kutz1, B Mueller1, P Schuetz1
1Kantonsspital Aarau, Aarau, Switzerland; 2Morton Plant Hospital, Clearwater, FL, United States; 3Pitié-Salpêtrière, Paris, France
Copeptin (pro-vasopressin) is a hormone derived from the same precursor protein as Vasopressin (AVP). Both hormones are secreted equimolar in response to physical stress and correlate with adverse clinical outcomes. In contrast to AVP, copeptin can be easily quantified by a sandwich immunoassay. Therefore, it serves as a surrogate marker for AVP and has emerged as a new prognostic marker in different settings including cardiovascular and infectious disease. The aim of this study was to evaluate the association between copeptin plasma concentrations and adverse outcomes in a large unselected study population seeking for emergency department (ED) care like under “real life” conditions.
This multicenter, observational cohort study consecutively included adult medical patients seeking for ED care in Switzerland, France and the USA during March 2013 to October 2014. We recorded initial clinical parameters and batch-measured the copeptin levels in a study population involving 7039 patients with available copeptin measures. We used logistic multivariate regression models (expressed in odds ratio, OR; 95% confidence interval, CI) and area under the receiver operating characteristic curve (AUC) to investigate the association of copeptin Plasma concentrations and different adverse outcomes (30-day all-cause mortality, intensive care unit [ICU] admission, initial treatment priority, main diagnoses and abnormal vital signs).
During a 30-day follow-up 329 (4.7%) participants reached the primary endpoint of death. In our logistic regression models adjusted for age and gender copeptin levels (log transformed with a base of ten) significantly predicted the 30-day risk of death (OR 3.35, 95%CI 2.78-4.04, AUC 0.78), ICU admission (OR 2.89, 95%CI 2.48-3.36, AUC 0.69) and high initial treatment priority (OR = 2.23, 95%CI = 2.04-2.43, AUC = 0,66). Furthermore we found significant associations between copeptin levels and abnormal vital signs including low blood pressure (OR = 2.71, 95%CI = 2.35-3.11, AUC = 0.70). Stratifying by main admission diagnoses, subgroup analyses showed best performance of copeptin levels for 30-day mortality prediction in metabolic disorders (OR 11.00, 95%CI 2.46-49.20, AUC 0.87) and acute infections (OR 6.90, 95%CI 4.13-11.53, AUC 0.80).
Based on our findings copeptin serves as a strong prognostic marker on ED admission and might help to improve risk stratification in unselected medical ED patients.
P377 The association of admission procalcitonin levels and adverse clinical outcome across different medical emergency patient populations: results from the multi-national, prospective, observational TRIAGE study
RS Sager1, YW Wirz1, DA Amin2, AA Amin2, PH Hausfater3, AH Huber1, S Haubitz1, A Kutz1, B Mueller1, P Schuetz1
1University Department of Medicine, Kantonsspital Aarau, Aarau, Switzerland; 2Morton Plant Hospital, Clearwater, FL, United States; 3Groupe Hospitalier Pitié-Salpêtrière, Paris, France
Although Procalcitonin (PCT) has been extensively studied in infectious conditions, the clinical relevance of PCT in unselected emergency department (ED) patients remains incompletely understood. We investigated association of admission serum PCT levels and adverse clinical outcomes in a large ED cohort from a previous multicenter study.
We prospectively enrolled 7132 adult medical patients seeking ED care in three tertiary care hospitals in Switzerland, France and the United States. We used adjusted multivariable logistic regression models to examine association of admission PCT levels and 30-day mortality, stratified by principal medical diagnoses and concomitant comorbidities. We calculated regression models across different clinically-established PCT cut-offs (0.05, 0.1, 0.25 and 0.5ng/ml).
During a 30-day follow-up 328 (4.9%) participants died. Mortality rate in the cut-off stratified groups were 1%, 3%, 7%, 14 and 17%, respectively. PCT had a high prognostic power for 30-day mortality with an area under the receiver operating characteristic curve of 0.74 (95%CI 0.72- 0.77; SE 0.0133). After adjustment for age, gender and main diagnoses, PCT cut-off levels were associated with a step-wise increase in risk of 30-day mortality with an adjusted odds ratio of 1.9, 4.5, 8.6 and 11.0 for pulmonal disease; 1.9, 4.7, 8.7 and 11.0 for cardiovascular disease and 1.9, 4.6, 8.8 and 11.4 for infectious disease, respectively. These associations were similar among different types of patients in regard to main diagnoses, comorbidities and age of patients.
In this large medical ED patient cohort, admission PCT was a strong and independent outcome predictor for 30-days mortality across different medical diagnoses. PCT may help to improve risk assessment in undifferentiated medical ED patients.
P378 Procalcitonin level in klebsiella pneumoniae MDR infections in icu
L Gottin, C Dell´amore, G Stringari, G Cogo, M Ceolagraziadei, M Sommavilla, F Soldani, E Polati
University Hospital, Verona, Italy
Infections due to K.Pneumoniae carbapenemase (KPC) are increasing . Trials analyzing the levels of Procalcitonin (PCT) in KPC infections are lacking. Aim of this study was to evaluate the levels of PCT in KPC infections compared with other Gram negative and verify if PCT levels correlate with sepsis severity.
From March 2012 to May 2013 133 adult patients with documented Gram negative bacteria infection, admitted to intensive care department were observed. In 53 patients KPC was isolated (KPC Group, KPCG), while in 80 patients other Gram negative bacteria caused the infection (Control Group, CG). All the patients were classified daily according to sepsis severity. Organ dysfunction was evaluated daily according to the SOFA score. PCT levels were detected daily by means of a quantitative method (Liaison). Microbiological coltures and imaging exams were performed according to clinicians decision. Statistical analysis was performed by means of the SPSS11.0 software.
As regards demographic data significant differences were showed except ICU LOS that was longer in KPCG. The main site of isolation of KPCs was the respiratory tract. According to the different sepsis severity diagnosis we found the following PCT levels (ng/ml). Sepsis: KPCG 0.9 ± 1.9, CG 6.6 ± 11.1 (p < 0.01); Severe Sepsis: KPCG 3.4 ± 6, CG 11.6 ± 19.8 (p < 0.01); Septic Shock: KPCG 8.9 ± 15.9, CG 30.5 ± 35.7 (p < 0.01) In KPC Group the mean PCT level in non-survivors was 7ng/ml, while in survivors was 2.7 ng/ml (p < 0.01). PCT mean values increased according to SOFA score increases.
Our data demonstrated that in septic patients with KPC infection PCT levels were significantly lower that those in septic patients with infection due to other Gram negative species. As regards outcome PCT levels confirmed to be related to severity of the disease with a mean level significantly higher in non-survivor compared to survivor. Mortality rate was higher in KPC Group compared to Control Group, but the difference was not significant.
See text for description
63.1 ± 18.3
65.3 ± 16.4
ICU LOS (days)
30.9 ± 33.4
16 ± 15.7
6 ± 4.4
6.9 ± 4.6
P379 Prognostic value of procalcitonin or lactate clearance, or both, for risk assessment in sepsis patients
M Meier1, T Baumgartner1, G Zurauskaité1, S Gupta2, B Mueller1, A Devendra2, P Schuetz1
1Kantonsspital Aarau, Aarau, Switzerland; 2Morton Plant Hospital, Clearwater, FL, United States
Several prognostic scores and biomarkers have been assessed for risk stratification in septic patients in intensive care units (ICUs). Serum lactate is a routinely used biomarker for the management of patients with sepsis and correlates with hypoperfusion and fluid resuscitation. Procalcitonin (PCT) is a bacterial infection marker and kinetics indicates the response to antimicrobial management. There is insufficient data comparing these two markers regarding outcome prediction. Herein, we compared the prognostic accuracy of lactate and PCT kinetics, and the combination of them, in a large, well defined US sepsis patient population.
This is an observational cohort study of adult patients with confirmed severe sepsis or septic shock included in a sepsis database from 14 different BayCare hospitals (Florida). All patients had PCT and lactate measurements on admission and during follow-up based on the treatment protocol. We used logistic regression and area under the curve (AUC) as a measure of discrimination of lactate and PCT with in-hospital mortality.
The in-hospital mortality rate of the 1075 included patients (mean age 66.9 years) was 18.8%. Concerning prognosis, the initial lactate level was a better mortality predictor (AUC 0.64) compared to PCT (AUC 0.55). For follow-up measurements, PCT (AUC 0.75) showed a better discrimination than lactate (AUC 0.73). When looking at biomarker kinetics, PCT increase was more strongly associated with fatal outcomes compared to initial levels alone (AUC 0.74) and was a better predictor compared to lactate kinetics (AUC 0.63). A joint logistic regression model combining follow-up measurements of lactate and PCT-kinetics showed a superior prognostic accuracy (AUC 0.82) compared to these markers alone.
P380 Impact of CRP, procalcitonin and CRP on mortality related with sepsis in ICU
D Mandaci, G Eren, F Ozturk, N Emir, O Hergunsel
Bakirkoy Dr.Sadi Konuk Training and Research Hospital, Istanbul, Turkey
Sepsis is known to be the leading cause of morbidity and mortality of ICU patients. APACHE 2, SAPS 2 ve SOFA scores are most frequently used for predicting mortality. Herein, it’s aimed to search for the effect of C-reactive protein (CRP), procalcitonin (PCT) and mean platelet volume (MPV) on mortality of sepsis in the ICU.
Retrospectively, 25 sepsis patients admitted to our ICU on May 2016 with at least 5 days of stay in the ICU were searched for APACHE 2, SAPS 2 and SOFA scores. The effect on mortality of CRP, procalcitonin and MPV values on the 1st, 5th and 10th days were analyzed with SPSS version 15 through receiver operating characteristic (ROC) curve analysis. Sensitivity, specificity, positive and negative predictive values were calculated.
Patients were between the ages of 18-79 years with a median of 53 and a female-male ratio of 56-44%. ROC analysis revealed that the last day MPV values were highly predictive for mortality (AUC: 0.99, p < 0.01). The cut-off for this value was calculated as 7.73, with a sensitivity of 90%, specificity of 100%, and positive predictive value as100%, negative predictive value as 53%. CRP values on the last day of ICU stay were predictive for mortality as well (AUC: 0.85, p < 0.01) with a cut-off value of 7.55, sensitivity of 92.3% but a specificity of 87.5% (positive predictive value: 92.3% and negative predictive value: 63.6%). Procalcitonin values of neither the first nor the last day of ICU stay were predictive of mortality. APACHE 2, SAPS 2 and SOFA were found to be well correlated with MPV values and the last day CRP values, but not with any of the procalcitonin values.
Together with APACHE 2, SAPS 2 and SOFA scores, CRP and MPV values are good predictors of mortality of sepsis in ICU. We consider a further study with a larger sample size to evaluate better the effect of procalcitonin in this issue.
1. Faix James D. Biomarkers of sepsis. Crit Rev Clin Lab Sci. 2013 Jan; 50(1): 23–36.
2. Tajarernmuang P, Phrommintikul A, Limsukon A, et al. The Role of Mean Platelet Volume as a Predictor of Mortality in Critically Ill Patients: A Systematic Review and Meta-Analysis. Critical Care Research and Practice, 2016. doi:10.1155/2016/4370834
P381 Serum procalcitonin in cirrhotic patients: a reliable biomarker of bacterial infection?
S Azaiez, S Khedher, A Maaoui, M Salem
Charles Nicolle Hospital, Tunis, Tunisia
Bacterial infection often leads to decompensated liver cirrhosis in cirrhotic patients. Its diagnosis should be swift, otherwise it is associated with a poor prognosis.
Our aim is to quantitate the various inflammatory markers in cirrhotics with and without obvious infectious disease.
A total of 80 patients admitted due to decompensated liver cirrhosis were included in this study. We explored the key epidemiologic, clinical and biological features of these patients.
54 patients (67,5%) were assigned to the infection group of which nine patients (16,6%) had positive blood culture. In this group, the following diagnoses were made : 34 lung infections, 11 spontaneous bacterial peritonitis, nine urinary tract infections, three skin infections, and two gastroenteritis. Three patients had an infection without an identified source.
The mean age for the infected patients (group 1) was 62.8 years and for the uninfected ones 63.4 years (group 2). There were higher levels of C reactive protein (CRP) and procalcitonine (PCT) in group 1 than in group 2 (a mean of 52.7 mg/ L and 1.3 ng/ mL versus 13,3 mg/l and 0,1 ng/mL respectively). The median of CRP for group 1 was 43,15 mg/ L. Infection at admission was associated with significantly higher levels of these proteins (p = 0.000). Leucocyte count was also higher in group 1 (p = 0.04).
49 patients had CRP levels below 43.15 mg/ L, wherein 25 (51%) had infections. In this particular group, CRP was significantly higher in infected patients (p = 0.000), unlike PCT (p = 0,06) and leucocyte count (p = 0.23).
Elevated PCT appear only in inflammations of an infectious etiology with systemic signs. Therefore in cirrhotic patients, procalcitonin determination seems appropriate for the diagnosis of severe infections but does not seem more reliable than CRP in other situations.
P382 The assessment of bacterial load in ICU nosocomial pneumonia
E Chernevskaya1, N Beloborodova1, A Bedova1, YU Sarshor1, A Pautova1, V Gusarov2
1Negovsky Research Institute of General Reanimatology, Moscow, Russia; 2Pirogov National Medical and Surgical Center, Moscow, Russia
Development of new microbial load biomarkers proceeds, but still - there is no perfect one. Procalcitonin (PCT) is commonly used and its level correlates with the extent of microbial invasion. Earlier it was found that aromatic microbial metabolites (AMM) - are associated with the severity and mortality of ICU patients [1, 2]. Also the effectiveness of the treatment can be evaluated by the AMM level . Experimental studies have shown their biological activity [3,4]. The aim of this work is to analyze different criteria of bacterial load in ICU patients with nosocomial pneumonia.
In prospective study 46 patients with nosocomial pneumonia admitted to ICUs were observed in the first day. After liquid-liquid extraction from serum samples 9 phenylcarboxylic acids (benzoic (BA), phenylpropionic, cinnamic, phenyllactic (PhLA), p-hydroxybenzoic, p-hydroxyphenyllactic, p-hydroxyphenylacetic (HPhAA), p-hydroxyphenylpropionic and homovanillic (HVA)) were measured using GC-MS (Trace1310-ISQ, Thermo). DNA was extracted from bronchoalveolar lavage (BAL) samples from 5 of 46 patients for the quantitative detection of nosocomial bacteria by the PCR-real time (IQ5, BIORAD), PCT and presepsin were measured on the 1, 3, 7-9 days after the diagnosis of pneumonia. Spearman’s correlation coefficient was found, data presented as medians with interquartile range (IR, 25-75%) using STATISTICA 10.
In serum samples of 46 patients the total concentration of 9 AMM was 3.4 (2.2-17.4) μ M that was higher (p < 0.05) than in healthy donors - 1.59 (1.46-1.85) μ M (n = 20). It correlated with APACHE II - 10 (6-18), SOFA - 3 (1-8) scores and mortality (41%): rs = 0.645, 0.666 and 0.717 respectively, p < 0.01. A closer analysis of 5 patient samples revealed the following correlations: the total concentration of 9 AMM correlated with PCT - 0.580, HVA with PCT and presepsin – 0.810 and 0.709, respectively, PhLA with presepsin-0.770, p-HPhAA with total DNA of bacteria and DNA Enterobactereacea in BAL– 0.635 and 0.724, p < 0.01.
The level of aromatic microbial metabolites in blood serum of ICU patients with nosocomial pneumonia reflects the microbial load as well as the quantity of bacterial DNA, PCT and presepsin.
Supported by Russian Science Foundation Grant 115-15-00110
1. Moroz VV et al. General Reanimatology 12(4): 37–48, 2016
2. Rogers AJ et al. PLoS One 9(1): e87538, 2014
3. Jankowski J et al. J. Am. Soc. Nephrol. 9(7): 1249–57, 1998
4. Beloborodova NV et al Anest. I rean. 61(3): 202–8, 2016
P383 Procalcitonin elimination during cytokine adsorption therapy in septic shock: a spin-off study of the ACESS trial
N Öveges1, I László1, M Forgács1, T Kiss1, P Hankovszky1, P Palágyi1, A Bebes1, B Gubán1, I Földesi1, Á Araczki1, M Telkes1, Z Ondrik1, Z Helyes2, Á Kemény2, Z Molnár1
1University of Szeged, Szeged, Hungary; 2University of Pécs, Pécs, Hungary
According to in vitro data, levels of pro- and anti-inflammatory mediators can be markedly decreased in septic shock by hemoperfusion using a novel cytokine adsorbent therapy (CytoSorb). However, the capacity and performance of the absorber over time has not yet been investigated. Our aim was determine elimination of procalcitonin (PCT) by the adsorbent in vivo, in patients with septic shock treated with CytoSorb for 24 hours.
The current study is a spin-off part of the ongoing “Adsorption Cytokines Early in Septic Shock”, the ACESS-trial. CytoSorb therapy was commenced early (<48h) after the onset of septic shock and performed for 24 hours. Blood samples were taken from the systemic circulation in every 6 hourly from the beginning (T0) to the end of CytoSorb therapy (T6, T12, T18, T24). Serum PCT, CRP, IL-1, IL-1ra, IL-6, IL-8, IL-10, TNF-α levels were measured. PCT levels were determined from blood taken simultaneously from the pre-, and post-adsorbent samples. The efficacy of PCT elimination was defined at every step by subtracting post-adsorbent (PCTpost) values from pre-adsorbent (PCTpre) values: Δ PCT = PCTpre-PCTpost.
Data were obtained from 7 patients and 8 treatments. Pre-adsorbent PCT levels showed a significant decline throughout the study (T0 = 12.2 [5.6-84.2], T6 = 6.8 [4.8-36.5], T12 = 6.7 [4.8-33.2], T18 = 5.9 [4.5-27.3], T24 = 5.1 [3.5-15.7] ng/ml; p = 0.011). Post-adsorbent PCT levels showed a similar pattern (p = 0.012). The efficacy of net PCT elimination (Δ PCT) was most effective at T0 = 11.7 [5.3-78.1] ng/ml, and showed a significant decline over time: T6 = 2.5 [1.4-14.9] ng/ml; T12 = 1.2 [0.3-6.1] ng/ml; T18 = 1.2 [0.5-4.8] ng/ml; T24 = 0.5 [-0.9-3.5] ng/ml; p = 0.004. This corresponded of a median of 90% elimination at T0, 30% at T6 and only 10% at T12 with no further change from T12-T24. This pattern showed consistency in every patient and was independent of the serum levels of PCT.
This study is the first to examine PCT elimination over time during CytoSorb therapy. According to these results, PCT elimination showed an exponential decline from 90% to a negligible degree after 12 hours. This phenomenon, on the one hand, shows the early efficacy of CytoSorb therapy, while on the other hand, it raises the question of changing the adsorbent earlier than the current practice of 24 hours.
ClinicalTrials.gov ID: NCT02288975
P384 qSOFA (quick SOFA) score, presepsin and procalcitonin for severity assessment in initial sepsis
E Spanuth1, H Ebelt2, B Ivandic1, R Thomae3, K Werdan2
1DIAneering GmbH, Heidelberg, Germany; 2Department of Medicine III, University Clinics Halle (Saale), Martin-Luther-University, Halle-Wittemberg, Germany; 3Mitsubishi Chemical Europe, Düsseldorf, Germany
The SOFA score is associated with an increased probability of mortality in sepsis. Assessment at admission in the ED requires several laboratory variables. The Third International Consensus Definitions for Sepsis and Septic Shock defined the qSOFA, which does not require laboratory tests and can be assessed at patient admission.
Objective: To compare sepsis biomarkers with SOFA and qSOFA to discriminate sepsis, severe sepsis or septic shock and to evaluate the association with increased risk of mortality.
66 Patients admitted to the ED with signs of sepsis and =/>2 SIRS-criteria were included. Severe sepsis and septic shock were defined according to current guidelines. qSOFA score was calculated using the recommended thresholds: respiratory rate =/>22/min, GCS score <15, stystolic blood pressure >100mmHG. Presepsin and procalcitonin were determined using the POC assay PATHFAST Presepsin (PSEP), LSI Medience, Japan and the BRAHMS luminescence immune assay (PCT).
SOFA and qSOFA, differentiated significantly between patients with sepsis (n = 30, mortality = 6.6%) and the high-risk group with severe sepsis or septic shock (n = 36, mortality = 36.1%). Discrimination between the groups revealed AUC values of 0.621, 0.627, 0.731, 0.740 and 0.781 for lactate, PCT, qSOFA, PSEP, and the combination qSOFA + PSEP, respectively. 15 patients died during hospitalization. AUC values of mortality prediction were 0.715, 0.558, 0.734, 0.758 and 0.803 for lactate, PCT, qSOFA, PSEP and qSOFA + PSEP, respectively. qSOFA scores =/>2 should identify greater risk of death or prolonged ICU stay. Discrimination between qSOFA <2 and =/>2 revealed AUC values of 0.756, 0.669 and 0.606 for PSEP, lactate and PCT.
Using the threshold =/>2 of qSOFA and =/>500 ng/L of PSEP, the combination qSOFA + PSEP detected 14 non-survivors (93%) and 33 (92%) patients of the high-risk group (n = 36), whereas qSOFA alone detected only 10 non-survivors (67%) and 21 patients of the high-risk group (58%).
The results demonstrated that the qSOFA score is not a standalone criterion for risk stratification in sepsis at admission. Simultaneous assessment by combining qSOFA and PSEP improved the validity significantly. The POC assay PATHFAST Presepsin showed superior performance compared to lactate and PCT.
Singer M et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801–810.
P385 Role of presepsin compared to c-reactive protein in sepsis diagnosis and prognostication
M. El-Shafie1, K Taema1, M El-Hallag1, A Kandeel2
1Cairo University, Cairo, Egypt; 2El-Sahel Teaching Hospital, Cairo, Egypt
Early identification of sepsis and its differentiation from non-infective SIRS are important for sepsis outcome. We intended to evaluate the use of presepsin in differentiating sepsis from non-infectious SIRS and its prognostic value compared to CRP.
We included 31 patients (median age 60 year old, 16 males) admitted with SIRS to El-Sahel Teaching Hospital, Egypt after excluding 21 patients with preadmission corticosteroids therapy, blood transfusion, immunosuppressive illness, and ICU length of stay (ICU-LOS) less than 24-hours. Patients were classified into non-infective SIRS group (13 patients) and sepsis group (18 patients). Presepsin, CRP and SOFA score were measured on admission and on days 2 and 4 of admission. The outcome parameters studied were ICU length of stay (ICU-LOS) and in-hospital survival.
Apart from temperature and AST which were significantly higher in sepsis group, the two groups were comparable. All the presepsin levels and CRP on days 2 and 4 were significantly higher in sepsis than in SIRS groups. The ICU-LOS was positively correlated with all the presepsin levels and with the CRP levels on days 2 and 4. All Presepsin values were significantly higher in survivors while none of the CRP levels were significantly different in survivors and non-survivors. The decrease of presepsin over time was significantly associated with better survival. It was found to be 70% sensitive and 91% specific for predicting survival in SIRS patients. This relation was not found in CRP levels.
We concluded that the presepsin may be used for early differentiation between sepsis and non-infectious SIRS and predict higher mortality.
P386 Urinary albumin/creatinine ratio as an early predictor of outcome in critically-ill septic patients
O Tayeh1, K Taema1, M Eldesouky1, A Omara2
1Cairo University, Cairo, Egypt; 2Electricity Hospital, Cairo, Egypt
Several cumbersome scoring systems were developed for prognosis and outcome prediction in sepsis. We intended in this study to evaluate the urinary albumin/creatinine ratio (ACR) as a prognostic predictor in sepsis.
We included 40 adult septic patients in a prospective observational study. We excluded patients with preexisting chronic kidney disease or diabetes mellitus. After clinical evaluation, urine spot samples were collected on admission and 24 h later for ACR1 and ACR2. Admission APACHE IV score and the highest recorded SOFA score of their daily estimation were considered. We also evaluated the need for mechanical ventilation, inotropic and/or vasoactive support, renal replacement therapy (RRT), and in-hospital mortality.
In a population with 63 (55–71) year old with 29 (72.5%) males, we found that the ACR2 is correlated with the SOFA score (r =0.4, P = 0.03). SOFA was higher in patients with increasing ACR [14(4.8–16.8) vs 5(3–8), P = 0.01]. None of the ACR measures was correlated with APACHE IV score. ACR2 was higher in patients who needed mechanical ventilation and inotropic and/or vasoactive support [140(125–207) and 151(127–218) mg/g respectively] compared to [65(47–174) and 74(54–162) mg/g], P = 0.01 and 0.009. None of the measured parameters was related to the need of RRT. ACR1, ACR2, APACHE IV and increasing ACR were predictors of mortality. The AUC for mortality prediction was largest for APACHE IV (0.90) then ACR2 (0.88). ACR2 of 110.5 mg/g was 100% sensitive and 86% specific to predict mortality.
We concluded that the urinary ACR may be used as a simple test for prognosis and mortality prediction in sepsis.
P387 Syndecan-1 (SDC1) and sphingosine-1-phosphate (S1P) are inversely associated in sepsis
MS Winkler1, M Holzmann1, A Nierhaus2, E Mudersbach3, E Schwedhelm3, G Daum4, S Kluge4, C Zoellner1
1Dep. of Anaesthesiology, University Medical Center Eppendorf, Hamburg, Germany; 2Dep. of Intensive Care Medicine, University Medical Center Eppendorf, Hamburg, Germany; 3Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 4Department of Vascular Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Sepsis is characterized by endothelial dysfunction. Crucial for endothelial function is the glycocalix (GLY), a carbohydrate-rich layer on the endothelial surface, which regulates vascular permeability, microcirculation and mechanotransduction. The GLY is anchored to the endothelium by glycoproteins and proteoglycans including Syndecan-1 (SDC1). Shedding of SDC1 has been observed in situations when the endothelium is damaged. Another key regulator of vascular permeability is sphingosine-1-phosphate (S1P) that upon binding to endothelial S1P receptor 1 strengthens barrier function. It has been observed that S1P is able to protect the GLY by inhibiting matrix-metalloproteinase (MMP) activity. We have recently observed decreased S1P levels in patients with sepsis, and here, addressed the question whether decreased S1P levels are associated with increased concentrations of SDC1 in serum of septic patients in the cohort we have previously studied for S1P levels .
The local ethics committee approved this study by acceptance of an amendment to our previous protocol. 59 ICU patients with sepsis or septic shock were enrolled. Blood samples were drawn at day 1 after admission and serum was prepared. Soluble SDC1 was measured by ELISA and S1P by mass spectrometry. The SOFA Score was used to assess disease severity. Twenty health controls were included.
SDC1 are increased and S1P levels are significantly decreased in sepsis patients when compared to controls. Highest SDC1 levels and lowest serum-S1P levels were found in patients with septic shock. The mean serum SDC1 concentration was 33 ± 24 ng/mL in controls, 196 ± 162 ng/mL in patients with sepsis and 260 ± 164 ng/L in patients with septic shock. Using linear regression analyses, S1P and SDC1 were found inversely associated (P < 0.001). The SDC1/S1P ratio was positively associated with the SOFA score (P < 0.01). By generating ROC curves for the SDC1/S1P ratio and the SOFA score to indicate septic shock similar areas under the curve (AUCs) were found with 0.77 for the SDC1/S1P ratio and 0.80 for the SOFA score.
We found increased SDC1 levels, which were associated with decreased serum-S1P levels in septic patients. SDC1 and S1P are inversely correlated and the ratio of SDC1/S1P reveals as valuable prognostic marker for septic shock.
1. Winkler, M.S., et al., Decreased serum concentrations of sphingosine-1-phosphate in sepsis. Crit Care, 2015.
P388 Serum sphingosine-1-phosphate (S1P) levels are rapidly decreasing during coronary artery bypassgraft
G Greiwe1, H Sawari2, E Schwedhelm3, A Nierhaus4, S Kluge4, J Kubitz1, R Jung5, G Daum6, H Reichenspurner2, C Zoellner1, MS Winkler1
1Dep. of Anaesthesiology, University Medical Center Eppendorf, Hamburg, Germany; 2Dep. of Cardiovascular Surgery, University Heart Center Hamburg-Eppendorf, Hamburg, Germany; 3Dep. of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 4Dep. of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 5Dep. of Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 6Dep. of Vascular Medicine, University Heart Center Hamburg-Eppendorf, Hamburg, Germany
Postoperative inflammation is associated with a sepsis like syndrome including endothelial barrier disruption, volume depletion and hypotension. Postoperative inflammation is especially associated with surgical procedures which require extracorporeal circulation. Sphingosine-1-phosphate (S1P) is a signaling lipid regulating permeability and vascular tone. In animal models S1P and S1PR1 specific agonists were able to limit trauma induced barrier disruption. Moreover in septic humans decreased serum-S1P levels could be identified as marker for sepsis severity. Low levels were predictive for septic shock. Here we were interested if S1P levels are altered by surgical trauma induced by cardiac bypass surgery.
26 patients with coronary heart disease planned for coronary bypass surgery were prospectively enrolled in this study. Serum samples were drawn pre-, post- procedure and on day 1 and day 4 after surgery. S1P concentration in μM was quantified by mass spectrometry. In addition we analyzed potential S1P sources: Red blood cells (RBC) and platelets. We further quantified levels of other inflammatory markers: C-reactive protein, procalcitonin, interleukin- 6 and von-Willebrand antigen.
Mean serum-S1P levels in patients before the procedure were 0.74 ± 0.2μM. S1P post-levels were lowest directly after surgery and dropped by 50% (0.37 ± 0.11μM). In recovery serum-S1P levels were increased to 0.60 ± 0.13μM on day 1 and was higher than pre levels on the fourth day 0.82 ± 0.18μM. There was no difference observed if patients were operated with or without extracorporeal circulation. In both groups the serum-S1P kinetics were similar, with significantly decreasing levels during surgery and increasing levels in recovery. In a correlation analysis serum-S1P levels correlated with its sources red blood cell (RBC) and platelet count. We did not observe a significant correlation of S1P levels with the dosage of vasopressors in the intraoperative phase or other inflammatory markers.
Cardiac bypass surgery induces a rapid decrease in serum-S1P levels. S1P might be a marker for early inflammation postoperative systemic inflammation, which is independent from other commonly used inflammatory markers.
P389 Can the biochemical and immunoinflammatory profile of patients sustaining high-energy tibial fractures predict the development of acute posttraumatic osteomyelitis?
M Groznik1, A Ihan2
1University Clinical Centre Ljubljana, Ljubljana, Slovenia; 2University of Ljubljana | Faculty of Medicine, Ljubljana, Slovenia
Early diagnosis of acute posttraumatic osteomyelitis (POM) is of vital importance to avoid devastating complications. Lack of specific and sensitive test as in myocardial infarct makes it difficult to diagnose POM. Serum inflammatory markers are not able to differentiate between response to infection and the host response to non-infection insult.
The prospective nonrandomised cohort study included 115 patients after high-energy injury to cruris required to be primary surgical treated. Values of biochemical and immunoinflamatory profile were measured on admission (ADD), first postoperative day (POD1) and fourth-postoperative day (POD4). Collected data from laboratory measurement and inpatient and outpatient medical records were analysed by descriptive statistics, univariate logistic regression and multivariate logistic regression with Firth correction and penalized regression.
The best predictors of PO on admission are T regulatory cells CD4 + CD25+, CRP and WBC counts, on POD1: WBC counts, CRP and PCT and on POD4: CRP, albumins, PCT and WBC counts. Performing logistic regression with Firth correction and multivariate penalized regression we found out that we can best predict development of PO by measuring CRP on ADD, POD1, POD4, PCT on ADD and POD4, albumins on POD4 and assessment of extent of soft tissue damage, transfusion rate, need of conversion primary external fixation to intramedullary (IM) nailing or locking plate fixation and patient’s physical status ASA 3-4 according to the American Society of Anesthesiologists. Our LASSO predictive model with cross-validated parameters has shown good performance (AUC = 0,75).
We can improve prediction of POM development by using perioperative inflammatory biomarkers PCT and CRP in combination with postoperative albumins and considering independent risk factors.
P390 Coenzyme q10 in acute influenza infection
LW Andersen, M Chase, MJ Holmberg, A Wulff, MN Cocchi, MW Donnino
Beth Israel Deaconess Medical Center, Boston, MA, United States
The goal of this investigation was to determine if acute influenza infection is associated with depletion of Coenzyme Q10 (CoQ10) and to determine any associations between CoQ10 levels and severity of illness and inflammatory biomarkers. CoQ10 is a key cofactor in the mitochondrial respiratory chain and may be depleted in acute critical illness. Prior investigations have found a correlation between depleted CoQ10 levels in patients with both septic shock and post-cardiac arrest and the inflammatory cascade. Statin medications have also been associated with decreased CoQ10 levels.
We analyzed serum CoQ10 concentrations of patients with acute influenza infection who were enrolled in a randomized clinical trial administering atorvastatin or placebo. Patients were enrolled at a single urban tertiary care center over 3 influenza seasons (12/2013 to 5/2016). Blood samples were obtained at enrollment prior to administration of any study drug. Healthy adult controls were used for comparison. We used Wilcoxon rank sum test to compare CoQ10 levels between influenza patients and controls. Correlations between CoQ10 levels and other inflammatory biomarkers and patient-reported severity of illness were assessed using Spearman correlation coefficient.
We analyzed CoQ10 from 50 patients with influenza and 29 healthy controls. Overall, patients with acute influenza infection had lower levels of CoQ10 compared to controls (0.61 ± 0.31 vs 0.77 ± 0.23 ug/mL, p = 0.004). There were significantly more patients in the influenza group with low CoQ10 levels compared to controls (48% vs 7%, p = 0.0001). There were significant correlations between CoQ10 levels in influenza patients and several inflammatory biomarkers: interleukin-2 (IL-2) (r = -0.297, p = 0.038), tumor necrosis factor alpha (TNF-α) (r = -0.352, p = 0.013) and vascular endothelial growth factor (VEGF) (r = 0.381, p = 0.007). There was no correlation between influenza severity of illness score at time of enrollment and CoQ10 levels.
We found that CoQ10 levels were significantly lower in patients with acute influenza infection as compared to controls and that CoQ10 levels had a significant correlation with several inflammatory biomarkers. Further study is warranted to define these relationships and identify potential targets for therapy in acute influenza.
P391 The research on effects of heparin-binding protein levels on early diagnosis in sepsis, severe sepsis and septic shock
Health Sciences University, Kocaeli Derince Traning Hospital, Kocaeli, Turkey
Sepsis is the body’s systemic inflammatory response to infection and can progress to severe sepsis, septic shock and ultimately multiple organ failure. Rapid detection of severe sepsis and septic shock is crucial for good outcome. Heparin- binding protein (HBP) is a multifunctional inflammatory mediator. HBP has been demonstrated in various infectious diseases caused by a wide array of bacteria. Procalcitonin and heparin -binding protein value may be useful for early diagnosis in sepsis, severe sepsis and septic shock patients in intensive care unit. The present study was conducted to determine the heparin- binding protein, procalcitonin level at early diagnosis in patients with sepsis, in comparison with C-reactive protein, IL-6 and TNF-alfa.
This was a prospective, observational of ICU patients with suspected infection, conducted Health Sciences University, Kocaeli Derince Traning Hospital’s ICU. The study was conducted aver a 7- month period between January and July 2016. Blood samples were taken on the first and second day of hospitalization, and the seventh day, on day of discharge or on the day of death.
Heparin-binding protein, PCT, TNF-alaf- IL-6 and C-reactive protein levels increased in parallel with the severity of the clinical condition of the patient. Heparin binding protein exhibited a greatest sensitivity and specificity in differentiating patients with sepsis. Also, when comparing all the data; HBP was the best predictor of early diagnosis sepsis and organ dysfunction (Our sturdy continues).
In the present study heparin binding protein was found to be a more accurate diagnostic parameter for differentiating sepsis and organ dysfunction.Heparin binding proetin may be helpful in the follow up of sepsis patients. HBP measurement in the ICU may help monitor treatment in patients with sepsis, severe sepsis and septic shock.
1. Herwald H, Cramer H, Mörgelin M, et al: M protein, a classical bacterial virulence determinant, forms complexes with fibrinogen that induce vascular leakage. Cell 2004; 116:367–379.
2. Linder A, Soehnlein O, Akesson P: Roles of heparin-binding protein in bacterial infections. J Innate Immun 2010; 2:431–438.
P392 A new scoring system for early diagnosis of ventilator-associated pneumonia: LUPPIS
M Haliloglu, B Bilgili, H Bilgin, U Kasapoglu, I Sayan, M Süzer, L Mulazımoglu, I Cinel
Marmara university hospital, Istanbul, Turkey
Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in critically ill patients and associated with increased mortality and morbidity, and prolonged mechanical ventilatory support and length of stay in the intensive care unit. The Clinical Pulmonary Infection Score (CPIS) based on chest X-ray has been developed to facilitate clinical diagnosis; however, this scoring system has a low diagnostic performance. In this study, the authors developed a new scoring system for early diagnosis of VAP called “Lung Ultrasound and Pentraxin-3 Pulmonary Infection Score (LUPPIS)” which is based on pentraxin-3 (PTX-3) levels and lung ultrasonography and evaluated the performance of this new scoring system.
This single center, observational, prospective study included 78 patients, who received therapy as an inpatient in the Intensive Care Unit between January 2015 and April 2016 and who were suspected of having VAP. At the day of study, an endotracheal aspirate was obtained for Gram staining and culture. PTX-3, procalcitonin (PCT), and other biomarkers were recorded. The diagnosis of VAP was confirmed according to either culture positivity or in culture negative patients, all clinical criteria and initiated or modified antibiotic regimen within 48 hours.
No significant differences were found between groups with respect to age, mechanical ventilation time, APACHE II score, and SOFA score (p > 0.05). PCT and PTX3 levels were significantly higher in the VAP (+) group (p < 0.001 and p < 0.001, respectively). The threshold for LUPPIS in differentiating VAP (+) patients from VAP (-) patients was >7 according to the highest Youden Index. In predicting VAP, LUPPIS > 7 (sensitivity of 84%, specificity of 87.7%) was superior to CPIS > 6 (sensitivity of 40.1%, specificity of 84.5%).
Early diagnosis of VAP currently remains challenging due to lack of a validated gold standard diagnostic method. The diagnosis and follow-up of pulmonary infections rely on the chest x-ray, although this is not feasible for critically ill patients in daily practice. Lung ultrasound (USG) is an important, simple, non-invasive, and cost-effective technique used in the diagnosis and differentiation of lung pathologies. Considering the overlap between sensitivity analysis and confidence intervals in the present study, LUPPIS appears to provide better results in the prediction of VAP compared to CPIS, and the importance of lung USG and PTX-3 is emphasized, which is a distinctive property of LUPPIS.
P393 An evaluation of the national early warning score in patients with unscheduled admissions to the intensive care unit
V Patel, S Shah, P Parulekar
Royal Sussex County Hospital, Brighton, United Kingdom
The National Early Warning Score (NEWS) is a UK-wide system measuring physiological variables to standardise evaluation of acute illness. We hypothesise that the NEWS may provide novel prognostic information for patients admitted to ICU.
We retrospectively assessed the NEWS and outcomes of emergency admissions in ward-based patients to the critical care unit in a UK tertiary care hospital. Data was obtained via patient notes and electronic records over a 6-month period. We evaluated: the NEWS trigger, the seniority of ward doctor reviewing the patient prior to ICU admission, Medical Emergency Team (MET) involvement, organ support requirements and mortality outcomes. in two distinct cohorts, NEWS > =7 versus NEWS < =6.
50 sets of notes were analysed. In the NEWS > =7 group, 65% of patients were seen by a ward registrar or above prior to critical care involvement. Only 42% of patients admitted to the ICU with NEWS > =7 triggered a MET alert, below the national standard. Over 90% of patients in both groups required at least one form of organ support, with a preponderance of basic cardiac and renal support in the NEWS < =6 group. The one-week mortality was higher in the NEWS > =7 group at 13% versus 4%, but 1-year mortality difference was negligible.
The RCP guidance for triggering an emergency review is poorly adhered to in our hospital. The necessity for organ support and one-year mortality were similar in both groups, suggesting that patients with NEWS < =6 are as vulnerable as the higher scoring group. This highlights a need to be identified more accurately. We propose the NEWS is combined with a nurse led observational “level of concern” score, supporting earlier referral to a senior physician.
See text for description
Percentage 1 week mortality
Percentage 1 year mortality
NEWS ≤ 6
NEWS ≥ 7
P394 National early warning scores (news) in sepsis – how does this score perform against other available markers routinely applied in the emergency department?
C Minton, J Patel, C Ejimofo, H Choi
University Hospital Lewisham, London, United Kingdom
Several scoring systems are used to risk stratify patients and alert staff to clinical deterioration. In the UK, the most widely used of these is the NEWS, a scoring tool based on physiological observations. There is increasing evidence that NEWS may be a useful diagnostic and prognostic tool in sepsis . A novel biochemical extension to the NEWS, using parameters from a blood gas (the metabolic score) was found to predict organ failure and death within 48 hours of admission .
We compared the predictive ability of NEWS with metabolic score for morbidity and mortality outcomes in patients with sepsis.
This retrospective observational study involved adult patients presenting to the emergency department of University Hospital Lewisham (UK) from September 2015-August 2016 with sepsis requiring inpatient care. Demographic data was gathered from the hospital electronic patient record system. NEWS was calculated from physical observations taken during the patients’ triage. The presence of co-morbidities and metabolic score were collected using a pro forma (completed by the clinician managing each case).
The primary outcomes were evidence of organ failure, escalation of care and death within 48 hours of admission. This information was gathered from the electronic patient record system.
Data was gathered from 140 patient attendances (mean age = 65 years [SD = 19.98], male = 65). 61 patients were identified as having evidence of organ failure, 12 patients required escalation of care and 22 patients died.
After controlling for demographic data, NEWS score at triage was predictive for the development of organ failure (p = 0.002) and death (p = 0.003) however it held no predictive value for escalation of care (p = 0.045). Metabolic score was predictive for death (p = 0.013) and the need for escalation of care (p < 0.001), however it was not predictive for the development of organ failure (p = 0.65).
Neither the NEWS or metabolic score can accurately predict the development of organ failure, escalation of care and death. We suggest that a combination of these scores should be used to aid risk stratification of septic patients presenting to the emergency department
1– Smith G et al. Resuscitation 84:465–70, 2013
2– Jafar A et al. Europ J Emerg Med 23: 130–6, 2016
P395 Sepsis-3 definitions predict hospital mortality better than sepsis-2 in oncological patients in a developing country: it’s time to move forward.
R Costa, P Caruso, P Nassar
AC Camargo Cancer Center, Sao Paulo, Brazil
We compared the new criteria of sepsis (Sepsis-3) with the previous criteria (Sepsis-2) to predict hospital mortality in oncological patients of a Brazilian Cancer Hospital. Any improvement on sepsis treatment shall begin with the early detection, especially in high-risk populations as the oncological patients in developing countries. Any diagnosis criteria that delay the diagnosis will impact on patients’ outcomes, especially in mortality.
Retrospective study conducted between 2009 and 2014 in a 55-bed ICU of a tertiary and teaching Cancer Hospital. We included all oncological patients admitted in the ICU that received the diagnosis of sepsis, severe sepsis or septic shock at the ICU admission by the attending physician. Mortality was compared across categories of both Sepsis-2 (sepsis, severe sepsis, shock septic) and Sepsis-3 definition (infection, sepsis, septic shock). A p value < 0.05 was considered statistically significant.
The medical records of 487 patients were collected from a prospectively recorded database. Mean age was 60 + 14 years, median SOFA was 7 + 7, respiratory tract infection was the most common cause of infection (21%, 101 patients), 398 patients (82%) presented solid tumor, 89 (18%) hematological malignancies and 297 (62%) had metastasis, median ECOG was 2 + 1.3 and 285 patients (59%) died in hospital. The mortality rate was progressively higher across categories of sepsis defined by Sepsis-3 consensus: infection with no organ dysfunction (28%); sepsis (55%) and septic shock (69%) (p < 0.001). There was no statistically significant difference among the categories of Sepsis-2 definitions, neither when they were analyzed separately: sepsis (50%); severe sepsis (57%) and septic shock (62%) (p = 0.2). One-hundred and fifteen patients (24%) did not meet sepsis criteria according to the Sepsis - 2 consensus but were diagnosed by ICU physicians as such. This group also showed a high mortality rate (49%).
In oncological patients of a Cancer Hospital located in a developing country, Sepsis 3 criteria were accurate in stratifying hospital mortality and in some aspects superior to the definitions previously used.
1. Kaukonen K et al.: N ENG JMED 2015; 371 (17): 1–10
2. Seymour et al.: JAMA 2016; 315 (8): 762–774
P396 Combining usage of national early warning score (NEWS) and rapid response team (RRT) in post HSCT patients might contribute to prognosis
J Fu1, J Jin1, Y Xu1, J Kong1, D Wu1, A Yaguchi2
1The First Affiliated Hospital of Suzhou University, Suzhou, China; 2Tokyo Women’s Medical University Hospital, Tokyo, Japan
Patients with early stage of post hematopoietic stem cell transplantation (HSCT) have a great risk of infectious complication. Sepsis contributes to morbidity and mortality in those patients. Therefore, it’s crucial to early detect sepsis and to treat with rapidly proper management. Our hypothesis is national early warning score (NEWS) and rapid response team (RRT) is useful to early detect and resuscitate sepsis in HSCT patients.
All post HSCT adult patients in sterile room unit who developed persistent fever for 3 days in our university hospital from January to December 2014 were included in this retrospective observational study. Patients were divided into two groups, 1) the control group and 2) the intervention group. Patients in the control group were treated with a local routine protocol. Patients in the intervention group had a local routine protocol treatment and were further evaluated with NEWS and RRT was activated simultaneously. RRT was activated when total NEWS score was exceeded 7 or individual item score was exceeded 3. The 90-day mortality, the number of ICU patients, SOFA score at ICU admission, the number of patients with vasopressor, the number of patients required mechanical ventilation, and days in post HSCT sterile room unit were compared between two groups. Values were expressed as mean ± SD. Data were analyzed by Mann–Whitney U-tests or Χ test. A p < 0.05 was considered as statistically significant.
There were 66 patients (35 men, 31 women; age median 37 (18-62)) in this study. The number of patients who admitted to ICU (6 vs. 3), SOFA score at ICU admission (7.6 ± 1.3 vs. 5.2 ± 1.2), the number of patient who required vasopressor (8 vs. 4) and the number of patient who required mechanical ventilation (6 vs. 3) were statistically higher in the control group than in the intervention group (p < 0.05). There were no significant differences in sex in 90-day mortality (17.6% vs. 15.6%) and days in post HSCT sterile room unit (17.4 ± 2.4 vs. 16.7 ± 2.8).
The NEWS monitoring and RRT did not statistically improved 90-days mortality in this study. However, the strategy using NEWS and RRT could contribute to early detect deteriorations and to timely ICU care in post HSCT patients who admitted in a special sterile room.
P397 Comparing criteria and scoring systems in ICU sepsis referrals
A Klonis, S Ganguly
New Cross Hospital, Wolverhampton, United Kingdom
Following publication of the Sepsis-3 review , we aimed to evaluate the awareness and use of the new qSOFA criteria for assessing patients with suspected sepsis and the use of SOFA scoring for subsequent evaluation. We also aimed to assess the correlation between MEWS and qSOFA, and the strength of the 24hr/48hr/mean/maximum SOFA and APACHE2 as predictors of mortality when compared to patient outcome.
This is a retrospective cross-sectional study over a period of 3 months. The patients’ electronic records were reviewed for the use and documentation of qSOFA, SOFA, or any other clinical parameters to justify sepsis requiring ICU input. If not present, the SIRS, qSOFA, 24hr, 48hr, mean & maximum SOFA scores were then calculated. Outcome (discharge vs death) was tested against the mortality risk scores. Inter-test agreement independent of outcome was also analysed. Pearson correlation and binary logistic regression analysis was used to assess for statistical significance.
Of the 214 patients admitted over the three-month period, 81% were admitted with a SIRS score of > =2 regardless of diagnosis. 33/214 patients (15.42%) were referred and admitted due to sepsis. None had SIRS or qSOFA documented either prior to or during their ICU admission. All had MEWS, APACHE2 and SOFA scores done only on ICU admission. They all had a retrospectively calculated admission qSOFA of 2 and their 24hr SOFA scores ranged between 5 and 16. Two patients admitted with sepsis had SOFA scores of 10 and 16 respectively, a qSOFA score of 2, but only 1 SIRS criterion. Three patients had a MEWS of 2, nine between 4-5 and twenty-two between 6-20; 94% of patients with sepsis admitted to ICU had MEWS of > =4. The top 5 clinical parameters used to justify ICU input due to sepsis were: reduced GCS, hypotension, tachycardia, pyrexia and Type 1 respiratory failure. The strongest correlation for patient outcome was with 48hr SOFA (p < =0.01), followed by mean SOFA (p < =0.01) and APACHE-II (p < =0.05). The best agreement between the mortality prediction scores was with APACHE2 and the mean SOFA score (p < =0.01), independent of outcome.
Despite the dichotomy of approach to sepsis, clinical judgement has remained constant. We observed that the 48hr SOFA had the best correlation with patient outcome. All septic patients had a qSOFA of 2, correlating well with a MEWS of > =4 seen in the majority of septic patients prior to their ICU admission, however we agree with Vincent et al  that until qSOFA is validated further, it should be used as a guide and not a replacement of SIRS.
1. Singer et al. Sepsis-3. JAMA. 2016
2. Vincent et al. qSOFA does not replace SIRS in the definition of sepsis. Critical Care 2016
P398 Automated microscopy for rapid directed antibiotic treatment of sepsis
M Kollef, C Burnham, B Fuller
Washington University School of Medicine, St Louis, Missouri, United States
Antibiotic resistance is increasing in frequency due to higher rates of inappropriate antimicrobial therapy and empiric use of broad-spectrum antibiotics.
We employed a real-time multiplexed automated microscopy system (ID/AST; Accelerate Diagnostics, Tucson, Arizona) capable of evaluating antibiotic susceptibility and resistance directly from positive blood culture broth in septic patients using automated phenotypic growth pattern analysis.
Pathogens included Klebsiella species (N = 17), E. coli (N = 16), Enterobacter species (N = 7), P. aeruginosa (N = 7), other Gram-negative species (N = 10), and Candida species (N = 11). Mortality was greater for patients treated with an inactive initial regimen (63.2% versus 6.5%; P < .001). Antimicrobial de-escalation occurred in 41 (63.1%). Time to patient identification and antimicrobial susceptibility using conventional methods was 51.4 hours [48.0, 54.6] versus 10.2 hours [8.3, 11.5] for ID/AST (see Fig. 13). For patients receiving an inactive regimen, ID/AST would have potentially allowed appropriate therapy to be administered a median of 35.8 hours sooner; while de-escalation could potentially have occurred 41.1 hours sooner.
P399 Comparison of the sonication method to roll plate method to diagnose central vascular catheter colonization and catheter–related infection in patients of ICU: a randomized prospective study
A Mavrommati, D Chatzilia, E Salla, E Papadaki, S Kamariotis, S Christodoulatos, A Stylianakis, G Alamanos
Alamanos KAT hospital, Kifisia, Greece
Catheter-related bloodstream infection (CRBSI) requires a positive blood culture and a positive result by the semiquantitative culture method (SQC) or the quantitative sonication method (SON). Our aim is to compare the yields of both techniques to detect the colonization and infection, in short and long term catheters in ICU patients.
We prospectively studied central venous antimicrobial catheter. Both methods were performed on tips cut into 2 equal segments each, to avoid loss of microbial colonies during serial examination and contamination. SQC method was performed by rolling the tip on a Columbia agar plate. Sonication was applied by placing the tip in 5 ml of 0.9NaCl, sonicating for 5 min, vortexing for 15s and culturing 0.1 mL of the fluid on a Columbia agar plate too. The cutoff for tip colonization was 15 cfu for SQC and 100 cfu for SON.
112 catheter tips (81long, 31short term) from 73 patients were included. The overall catheter tip colonization was 38.4% (43/112). The SON method detected colonization in 39/43 (90.6%) and SQC in 25/43 (58.1%) catheters p < 0.01). 18/112 patients (16%) had a definite CRBSI according to the current guidelines. 17/18 (94.4%) were detected by SON method and 9/18 (50%) by SQC method. Most commonly bacteria were Enterobacteriaceae, isolated by SON in 54.5% and by SQC in 45.5%, followed by coagulase-negative staphylococci in 22.7% and 11.4% respectively. SON detected Candida spp. in 8.1% while SQC failed.
Our findings, unlike previous studies, imply superiority of the SON method over SQC, in detection of catheter colonization and CRBSI. A hypothetical explanation is based on the prolonged sonication time of 5 min (instead of the usual 1 min), which probably enhances detachment of gram (-) bacteria that as endoluminal bacteria are more difficult to isolate by SQC. Especially for long term catheters, where colonization by gram (-) bacteria is most often, according to the literature, the sonication method may be prove particularly useful for colonization detection and CRBSI diagnosis. Further investigation is envisaged to explore the potential of the method.
1. Slobbe L et al.:J Clin Microbiol. 2009;47:885–888.
2. Erb S et al.:Clin Infect Dis 2014;59:541–544.
3. Mermel LA et al.: Clin Infect Dis 2009; 49 :1–45
P400 Retrospective analysis of microbiological samples at ICU admission
M Simoes, E Trigo, N Silva, P Martins, J Pimentel
Centro Hospitalar Universitario de Coimbra, Coimbra, Portugal
Hospital-acquired (or nosocomial) infections are important causes of morbidity and mortality despite improved antimicrobial therapy, supportive care, and prevention. However, due to aging, comorbidities and repeated contact with healthcare facilities, many patients are already infected with multidrug-resistant (MDR) pathogens at the time of ICU admission.
Retrospective analysis of microbiologic exams taken at admission in a ICU over one year, using data obtained from microbiology laboratory. Characterization of positive samples regarding pathogens identified and clinical setting (community vs hospital acquired).
2788 samples were obtained in 510 patients admitted to the ICU during 2015. Regarding the type of sample, 23.6% were tracheal aspirate cultures, 57.6% blood cultures and 18.7% urine cultures. We collected 560 positive samples, obtained from 280 patients. From the tracheal aspirate cultures, 38.3% were positive. The most frequent pathogen was S. aureus, found in 74 samples – 15 of which were oxacilin resistant. 8 of these patients were admitted from the ER. The other were transferred from wards: 3 from medical wards and 4 from surgical wards, with an average lenght of stay (LOS) before ICU admission of 5 days. 9 samples were positive for A. baumanii, 1 admitted from ER, 3 from surgical and 5 from medical wards. In 7 samples were found ESBL positive pathogens, 5 coming from surgical wards, 1 from ER and 1 from medical ward. From the blood cultures, 11.6% were positive. The most common pathogen was S. epidermidis in 46 samples. Regarding MDRs, we found 9 MRSA, 5 ESBL positive germens and 4 A. baumanii. The MRSA positive samples were obtained from patients coming mostly from surgical wards (5), followed by medical wards (2) and ER (2), with an LOS before ICU admission of 9.4 days. The ESBL positive pathogens were found in 3 patients admitted from ER and 2 patients from surgical wards, with average LOS previous to admission of 4.6 days. A. Baumanii was identified in 2 patients coming from medical wards, 1 from surgical and 1 from ER. In urine samples the most frequent germen was E. coli, found in 7 samples; and K. pneumoniae, found in 5. From these, 3 were ESBL positive, 2 coming from surgical wards and 1 from ER. The average LOS before ICU admission was 5.0 days. 2 samples were positive for A. baumanii. MDR Pseudomonas aeruginosa were found in 2 samples.
MDRs were found at ICU admission in 54 samples (9.6% of all positive samples). 44.4% came from surgical wards and 33.3% from ER. The number of MDR found in patients admitted from ER probably results from repeated contact with healthcare facilities. Surgical patients are more prone to MDR infections.
P401 Microbiological yield of bronchoalveolar lavage in the setting of veno-venous ECMO
D Baily1, LA Curran2, E Ahmadnia2, BV Patel2
1Royal Brompton Hospital, London, United Kingdom; 2Royal Brompton and Harefield NHS Trust, London, United Kingdom
Whilst bronchoalveolar lavage (BAL) in the context of adult extracorporeal membrane oxygenation (ECMO) has been shown to be safe , there is a paucity of data regarding the microbiological yield and microbiota of BAL in this setting. In community acquired pneumonia (CAP), BAL may be of additive diagnostic value in around 50% of patients , with a similar yield in ventilator associated pneumonia (VAP) . The aim of this study was to describe the positive microbiological BAL results and the yield of BAL in the context of adult veno-venous ECMO (VV-ECMO) at a large UK ECMO centre.
A retrospective analysis was conducted of all BAL microbiological results of patients supported with VV-ECMO at a UK specialist centre for severe acute respiratory failure. Data were collected for the period April 2014 to July 2016, restricted to the initial diagnostic BAL done on admission to this centre.
Of the 85 patients treated with VV-ECMO, BAL was performed on admission in 71/85 cases (84%). The vast majority (83/85) were on antibiotics for suspected bacterial pneumonia. A total of 58 positive microbiological results were obtained from 45/71 patients, giving an overall BAL yield of 63%. The bacterial yield from BAL was 18%. Fungi were isolated from 23 patients (32%), respiratory viruses from 19 patients (27%), and bacteria from 13 patients (18%). The most commonly isolated fungi were species of Candida (predominantly C. albicans), found in 18 patients. Aspergillus was isolated from 4 patients (6%), but in no case was it the only organism identified. Influenza A, found in 11 patients (15%), accounted for more than half of all the positive virology results. Staphylococcus aureus was the most common bacterium isolated (7%), closely followed by Pseudomonas aeruginosa (6%).
BAL on admission to a specialist centre provides an acceptable overall microbiological yield in the context of VV-ECMO (as compared with previous data for CAP and VAP). The bacterial yield is low. The finding of a positive BAL fungal result should be correlated with the clinical context.
 Sharma NS et al. Respir Care 2016 May;61(5):646–51
 Van der Eerden et al. Eur J Clin Microbiol Infect Dis (2005) 24: 241
 Medford et al. J Crit Care 2009 Sept;24(3):473.e1–6
P402 Catheterization, bacteriuria and urinary tract infection in coronary care unit
D Adukauskiene1, J Cyziute2, A Adukauskaite3, D Pentiokiniene1
1Hospital of Lithuanian University of Health Sciences, Kaunas, Lithuania; 2Lithuanian University of Health Sciences, Kaunas, Lithuania; 3Innsbruck Medical University Hospital, Innsbruck, Austria
The aim was to estimate the rate of urinary tract infection in bacteriuria, duration of urinary tract infection treatment and length of stay also associated factors with poor outcome in Coronary Care Unit patients.
Retrospective analysis of 57 patients data with bacteriuria treated in Coronary Care Unit in Hospital Kaunas Clinics of Lithuanian University of Health Sciences during 5 years was carried out.
Urinary tract infection was revealed in 52 patients (91.2%) of 57 with bacteriuria, p < 0.05. Mean length of stay in Coronary Care Unit in case of bacteriuria as colonisation was 3.6 ± 1.8 days, in bacteriuria as urinary tract infection was 10.67 ± 3.9 days, p < 0.05. Length of stay in Coronary Care Unit was 10.68 ± 5.3 days if urinary tract infection was caused by bacteria, 27.75 ± 12.3 days by fungi, p < 0.05. Duration of urinary tract infection in 24 patients with adequate empirical antibacterial treatment was 9.9 ± 4.7 days, but 15.7 ± 3.3 days in 28 patients with inadequate antibacterial treatment, p < 0.05. Length of stay in Coronary Care Unit was 3.3 ± 2.1 days in case of adequate empirical antibacterial treatment, 14.7 ± 5.3 days when inadequate, p < 0.05.
Twenty – one patient (40.4%) of 52 with urinary tract infection has died in Coronary Care Unit. Seventeen patients (39.5%) of 43 have died in group > = 65 years, 4 patients (44.4%) of 9 in group 50 – 64 years, but all 5 patients < 50 years have survived, p < 0.05. 5 patients (45.5%) of 11 with diabetes mellitus have died (95%; OR 1.3; CI 0.33 – 4.99; p < 0.05). Twenty – one patient (42.9%) has died of all 49 with urinary bladder catheterization, 8 patients (25%) of 32 with short – term urinary bladder catheterization, 13 patients (76.5%) of 17 with long – term urinary bladder catheterization, but none of 8 patients without of it, p < 0.05.
Rate of urinary tract infection in bacteriuria was 91.2%. Length of stay in Coronary Care Unit was longer in case of bacteriuria due to urinary tract infection and fungi as pathogens of it. The length of urinary tract infection treatment as well as stay in Coronary Care Unit was shorter in case of adequate antibacterial treatment. The mortality rate of urinary tract infection in Coronary Care Unit was 40% related to age > = 50, diabetes mellitus, urinary bladder catheterization, especially long – term.
P403 Bacterial colonization in tracheoventilated patients
F Righetti, E Colombaroli, G Castellano
Intensive Care Unit. St. Boniface Hospital, Verona, Italy
Ventilator-associated pneumonia (VAP) is an infection related to high mortality, high costs for antibiotic therapy and long hospital stays and rehabilitation programs. Our retrospective and observational study aims to evaluate the prevalence of bacterial colonization of the airways in tracheostomized and ventilated patients, affected by motoneuron disease [1, 2].
22 tracheostomized patients, ventilated for 24 hours a day, at home, affected by motoneuron disease, followed in the period 2015-2016, tracheostomic cannula change every 90 days, tracheobronchial sample and chest X-ray performed every year in absence of VAP. In the considered period, no patients was hospitalized nor has received targeted antibiotic therapy. It was compared the prevalence of bacterial colonization in 2015 compared to 2016.
In 2015 the prevalence of Pseudomonas Aeruginosa was 64%, of MRSA (Stafilococcus Aureus methicillin resistant) 35%, of Klebsiella Pneumoniae 5% and of Enterobacteriacee (Providencia, Serratia, Proteus, Enterococchi) 52%. 52% of patients have polymicrobial infections. In 2016 the prevalence of Pseudomonas Aeruginosa was 63%, of MRSA 45%, of Klebsiella Pneumoniae 9% and of Enterobacteriacee 54%. 54% of patients have polymicrobial infections. In any of the 2 periods are found colonizations by totiresistant bacteria.
Comparing the 2 periods, we found that there aren’t substantial percentage differences of prevalence of bacterial colonization by Gram negative bacteria; on the contrary there is an increase of bacterial colonization by Gram positive bacteria - MRSA. Our study shows that tracheostomized patients, ventilated for 24 hours a day at home do not develop totiresistant colonization.
1. Behnia M. et al.: Nosocomial and ventilator-associated pneumonia in a community hospital intensive care unit: a retrospective review and analysis. BMC Res Notes. 2014 Apr 11;7:232
2. Morar P. et al.: Oropharyngeal carriage and lower airway colonisation/infection in 45 tracheotomised children. Thorax. 2002 Dec;57(12):1015–20
P404 Lower bacterial growth after induction of endotoxin-tolerance in a porcine intensive care sepsis model
F Wilske1, P Skorup1, M Lipcsey2, K Hanslin2, A Larsson1, J Sjölin1
1Uppsala University, Uppsala, Sweden; 2Uppsala University, Department of Surgical Sciences, Uppsala, Sweden
Endotoxin tolerance leads to an attenuated inflammatory response at a second hit . From this it was hypothesized that bacterial killing might be affected similarly. If so, studies whether this might be of importance for the choice of antibiotics are warranted. In a previous study it has been shown that bacterial elimination and killing in bacteraemic animals occur in the spleen and liver . Therefore, the objective of this study was to compare the killing of bacteria in the spleen and liver in animals made endotoxin tolerant by a 24h-endotoxin infusion with that in animals not exposed to endotoxin.
The endotoxin exposed group (Exp) (n = 18) were, prior to the bacterial exposure, given 0.063 μg/kg/h endotoxin during 24 h. Thereafter, an Escherichia coli intravenous infusion of 8.3 log10 Colony Forming Unit (CFU)/h was administered for 3 h. The endotoxin unexposed group (Unexp) (n = 18) was given an identical bacterial challenge but without the preceding exposure of endotoxin. The animals were observed for signs of sepsis and inflammatory response and treated in accordance with an intensive care protocol . Blood cultures were obtained hourly. After 6 h the animals were killed by a potassium chloride injection. Biopsies for quantitative culture were taken from the liver and spleen immediately post mortem.
All animals developed signs of sepsis. Peak TNF-α levels 1 h after start of the bacterial infusion were 2.27 ± 0.13 and 4.17 ± 0.13 log10 pg/ml (mean ± SE) in the Exp and Unexp groups, respectively. Clearance of bacteria from the blood was rapid and within 1 h. The Exp group demonstrated a significantly increased killing and attenuated growth of bacteria in the spleen and a similar trend in the liver. Mean bacterial growths in the spleen of the Exp and Unexp groups were 3.16 ± 0.13 and 3.73 ± 0.17 log10 CFU/g (mean ± SE), respectively (p = 0.01). Mean bacterial growths in the liver of the Exp and Unexp groups were 2.01 ± 0.18 and 2.40 ± 0.23 log10 CFU/g (mean ± SE), respectively (p = 0.20).
Contrary to the hypothesis the reduced cytokine response characteristic for endotoxin tolerant animals was not associated with a reduced bacterial killing in the spleen and the liver. This indicates that these processes do not run in parallel in vivo. The effect on bacterial killing after more prolonged activation of inflammatory and anti-inflammatory responses needs further investigation.
 Castegren et al. Shock 37:501–510, 2012
 Skorup et al. PLoS ONE, e90441, 2014
P405 Clinical predictors and outcome of Klebsiella pneumoniae bacteremia in a regional hospital in Hong Kong
M Man1, HP Shum1, YH Chan1, KC Chan2, WW Yan1, RA Lee3, SK Lau4
1Department of ICU, PYNEH, Hong Kong, Chin; 2Department of Anaesthesia and Intensive Care, Tuen Mun Hospital, Hong Kong, China; 3Hong Kong East Cluster Department of Clinical Pathology, Hong Kong, China; 4Department of Microbiology, The University of Hong Kong, Hong Kong, China
Klebsiella pneumoniae (KP) infection is associated with high morbidity and mortality in different clinical settings. Multi-drug resistance associated with extended spectrum beta-lactamase (ESBL) among KP is endemic worldwide. Our study aims to evaluate the clinical characteristics and outcomes of patients with KP bacteraemia in the critical care and general ward settings.
Adult patients admitted to a regional hospital in Hong Kong from 1 January 2009 to 30 June 2016 (7.5 years) with KP bacteremia were included. Demographics, disease severity, clinical features, microbiological characteristics and outcome were analyzed.
Among the 853 patients, 178 (20.9%) required critical care and 176 (20.6%) died within 30 days of hospital admission. 30-day survivors were younger (p < 0.001), had lower disease severity (defined by SOFA score) (p < 0.001), presented with hepatobiliary sepsis (p < 0.001) or urosepsis (p < 0.001), less septic shock (p = 0.013) or requirement of invasive organ support (p < 0.001) and received appropriate empirical antibiotics (p < 0.001). Cox regression analysis showed that respiratory tract (HR = 2.99; 95% CI = 2.061-4.337;p = <0.001), gastrointestinal tract (excluding hepatobiliary system) infection (HR = 2.763; 95% CI = 1.761-4.337; p = <0.001), use of mechanical ventilation (HR = 2.202; 95% CI = 1.506-3.221; p = <0.001), medical case (HR = 1.830; 95% CI = 1.253-2.672; p = 0.002), inappropriate empirical antibiotics (HR = 1.716; 95% CI = 1.267-2.324; p = <0.001), female (HR = 1.699, CI = 1.251-2.307, p < 0.001), age >65 (HR = 1.692; 95% CI = 1.160-2.467; p = 0.006) and presence of solid tumor (HR = 1.457; 95% CI = 1.056-2.009; p = 0.022) were independent risk factors for 30-day mortality. Unexpectedly, presence of diabetes mellitus was associated with a better 30-day survival (p = 0.002). ESBL-producing strains were identified in 102 patients (12.0%). Non-hepatobiliary sepsis, use of systemic steroid within 30 days before positive blood culture, presence of solid tumor and use of central venous catheter independently predicted the occurrence of ESBL KP bacteremia. However, presence of an ESBL strain was not associated with higher 30-day mortality.
KP bacteremia is associated with high 30-day mortality. Site of infection, patient’s comorbidities and appropriate use of empirical antibiotics are important predictors of patients’ outcome. Early empirical antibiotics in high-risk groups is warranted.
P406 Mortality rate of ventilator-associated pneumonia patients receiving tigecycline in intensive care unit, university hospital, Thailand
P Dilokpattanamongkol1, P Thirapakpoomanunt1, R Anakkamaetee1, P Montakantikul1, V Tangsujaritvijit2
1Faculty of Pharmacy, Mahidol University, Bangkok, Thailand; 2Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Several studies have shown that the use of tigecycline, especially in ventilator associated pneumonia (VAP) patients, was significantly associated with increased risk of all-cause mortality. However, tigecycline is one of the options for multidrug resistant Acinetobacter baumannii which is a growing problem in Thailand. Moreover, there have not been any studies showing such correlation at a University Hospital, Thailand. The purpose of this study was to investigate the mortality rate and the length of hospital stay of Acinetobacter baumannii VAP patients receiving tigecycline compared with other antibacterial agents.
A retrospective study chart review was performed in patients admitted to Intensive Care Units, University Hospital during 2007 and 2015 and received the treatment for Acinetobacter baumannii VAP. Primary outcome, mortality rate, and secondary outcome, ventilator days, in both groups were collected.
There were 126 patients; 80 patients in tigecycline group and 46 patients in non-tigecycline group. We selected only 41 Acinetobacter baumannii VAP patients in each group with matched baseline characteristics. The mortality rate of tigecycline group was significantly higher than non-tigecycline group (73.20% and 46.30% respectively, P = 0.013). The median length of hospital stay was also significantly higher in tigecycline group than non-tigecycline group (46.99 days and 30.24 days respectively, P = 0.004).
The use of tigecycline in Acinetobacter baumannii VAP patients increased the mortality rate and the length of hospital stay compared with the use of other antibacterial agents. However, a prospective cohort study with larger sample size is necessary.
1. Stein GE, Babinchak T. Review: Tigecycline: an update. Diagn Microbiol Infect Dis 2013; 75: 331–6.
Walker T. FDA warns of increased death risk with tigecycline use. 2013: 30.
2. Pongpech P, Amornnopparattanakul S, Panapakdee S, et al. Antibacterial activity of carbapenem-based combinations againts multidrug-resistant Acinetobacter baumannii. J Med Assoc Thai 2010; 93 (2):161–71.
P407 Outbreak of colistin resistant bacteria in a tertiary care center-analysis of risk factors and outcome
S Sinha, J Pati, S Sahu
Apollo hospitals, Bhubaneswar, India
The incidence of carbapenem resistant enterobacteriacae (CRE) has been steadily rising . The morbidity, mortality and financial implications of such patients are significant. We recently had few reports of colistin resistance in our centre. This prompted us to analyse the risk factors for the outbreak of pan drug-resistant (PDR) organism.
We did a retrospective analysis of the case records of the patients who had any culture report positive for pan drug resistant (PDR) organisms. Cultures were done in our centre using VITEK 2 compact for all specimens. We followed the report of VITEK-2 and EUCAST breakpoints were followed (S < = 2, R > =2) for Enterobacteriacae. Pseudomonas and Acinetobacter isolates were considered resistant to colistin if the MIC > = 8 and 4 respectively. Their APACHE II score on admission, all culture reports, antibiotics received, length of stay in ICU and hospital along with outcome were scrutinized.
There were total 10 isolates of PDR organisms in 8 patients. Five patients had received prior colistin therapy due to growth of carbapenem resistant bacteria isolates while 3 cases had no prior colistin treatment. Two out of 5 such cases had colistin monotherapy. Among 10 such isolates, there was Klebsiella pneumonia in 7, Pseudomonas aeruginosa in 2 and Acinetobacter baumanii in one case. Among these 7 isolates were considered to be coloniser and three were infective pathogens. These PDR isolates were associated with CAUTI (5), tracheitis (2), bacteremia (1), meningitis (1) and soft tissue infection (1). Average APACHE II score was 24 indicating sicker patients with multiple co-morbidities and organ dysfunction. Mean age of the patients was 50.4years. Average length of hospital stay was 42.8 days. Four of these patients died while other 4 were discharged home. Six of the 8 patients belonged to neurosciences (stroke and traumatic brain injury) and had overall poor status with Glassgow coma scale (GCS) <8 with long hospital stay.
Critically ill patients with longer hospital stay are more likely to get affected by PDR organisms. Patients requiring long-term rehabilitation should be cared for in dedicated centers. Culture reports should be judiciously interpreted to differentiate between colonizer and infective pathogen before treatment. Widespread indiscriminate use of colistin to treat CRE and other gram negative organisms can lead to emergence of PDR organisms. Strict implementation of antibiotic stewardship programme are essential to limit use and prevent abuse of colistin.
1. Antoniadou A, Kontopidou F et al:Colistin-resistant isolates of Klebsiella pneumoniae emerging in intensive care unit patients: first report of a multiclonal cluster. J Antimicrob Chemother. 2007 Apr;59(4):786–90.
P408 Where are we going? Analysis of MDR and ESBL E. coli monobacteremia in ICU of university hospital
D Adukauskiene, D Valanciene, A Dambrauskiene
Hospital Kaunas Clinics of Lithuanian University of Health Sciences, Kaunas, Lithuania
The aim of study was to analyze multidrug-resistant (MDR) and extended spectrum beta – lactamases (ESBL) producing E. coli strains of monobacteremia also associated factors with length of stay in Intensive Care Unit (ICU) > =7 days and mortality.
The retrospective data analysis of patients (pts) treated in surgical and medical ICU of Kaunas Clinics with E. coli positive blood culture during 2005-2015 was carried out.
There were found 87 (70.7%) MDR strains among 123 cases of E. coli monobacteremia (P = 0.046). Rate of MDR strains during study period was: 6 (42.9%) cases in 2005, 12 (66.7%) in 2010, 12 (85.7%) in 2015 (P = 0.027, RR = 17.324).
There were found 57/87 (65.5%) cases of ESBL producing strains among E. coli MDR strains (P = 0.04). Rate of ESBL producers during study period was: 2 (16.7%) cases in 2005, 7 (58.3%) in 2010, 10 (76.0%) in 2015 (P = 0.03, RR = 14.856).
28/57 (49.1%) pts with both MDR and ESBL E. coli strain stayed in ICU > =7 days. All 28 (100%) pts had SOFA score > =13, were mechanically ventilated > =3 days and were in shock, respectively (P = 0.001), 25/28 (89.3%) were admitted from emergency department (P = 0.03).
79/87 (90.8%) pts with E. coli MDR strain have died. All 79 (100%) pts were mechanically ventilated (P = 0.04), 78 (98.7%) were in shock (P = 0.001, OR = 5.909, CI95% = 2.176–16.049), 68 (81.0%) had diabetes mellitus (P = 0.03), 66 (78.6%) had renal dysfunction (P = 0.046), 59 (70.2%) had SOFA score > =13 (P = 0.032, RR = 12.00) and 54 (65.5%) pts had ESBL strain (P = 0.04).
54/57 (94.7%) pts with ESBL producing E. coli strain have died. All these 54 (100%) pts were mechanically ventilated (P = 0.001), were in shock (P = 0.001), 50 (92.6%) had SOFA score > =13 (P = 0.01), 45 (83.3%) had diabetes mellitus (P = 0.02) and 35 (64.8%) pts had renal dysfunction (P = 0.04).
MDR E. coli was found in 2/3 of all E. coli monobacteremia strains, 2/3 of them were ESBL producers. During 11 year rates of both MDR and ESBL strains were constantly increasing: MDR doubled, ESBL have increased in 4.5 times. Associated factors for stay in ICU > =7 days were admission from emergency department, ESBL producing strain, mechanical ventilation > =3 days, shock, SOFA score > =13. Very high mortality rate of E. coli monobacteremia due to MDR or ESBL strain was associated with diabetes mellitus, ESBL producing strain, mechanical ventilation, shock, renal dysfunction, SOFA score > =13.
P409 E. coli bacteremia in intensive care unit: associated factors with length of stay and mortality
D Adukauskiene, D Valanciene, A Dambrauskiene
Hospital Kaunas Clinics of Lithuanian University of Health Sciences, Kaunas, Lithuania
The aim of study was to analyze antimicrobial resistance of E. coli in monobacteremia and associated factors with length of stay in Intensive Care Unit (ICU) > =7 days and mortality.
The retrospective data analysis of patients (pts) treated in surgical and medical ICU of Kaunas Clinics with E. coli positive blood culture during 2005-2015 was carried out.
There were found 123 cases of E. coli monobacteremia, and this group was homogenous in point of gender, age, comorbidities, source of bacteremia (P > 0.05).
104 (84.6%) strains of E. coli were resistant to ampicillin, 94 (76.4%) - ampicillin/sulbactam, 90 (73.2%) - gentamicin, 88 (71.5%) – cefotaxim, 57 (46.3%) – ciprofloxacin, 56 (45.5%) - piperacillin, 34 (27.6%) - piperacillin/tazobactam, 29 (23.6%) - amikacin. Resistance to carbapenems was 0/123 (0%). 87/123 (70.7%) E. coli strains were found to be multidrug-resistant (MDR) (P = 0.046). 57/87 (65.5%) E. coli MDR strains were producers of extended spectrum beta-lactamases (ESBL) (P = 0.04). 32/123 (26.0%) pts stayed in ICU > =7 days. 30 (93.6%) pts among them were on mechanical ventilation > =3 days (P = 0.004, RR = 23.097), 29 (90.6%) had SOFA score > =13 (P = 0.036, RR = 18.762), 28 (87.5%) were in shock (P = 0.019, RR = 2.956), 25 (78.13%) were admitted from emergency department (P = 0.049, RR = 19.987), 23 (71.9%) had MDR strain (P = 0.049, RR = 15.085), 19 (59.4%) had ESBL strain of E. coli (P = 0.049, RR = 12.476). 88/123 (71.5%) pts with E. coli monobacteremia have died. Mortality rate’s dynamic during study period was: 12 (66.7%) cases in 2005, 13 (72.2%) in 2010 and 13 (92.9%) in 2015 (P = 0.012). 84 (95.5%) pts had MDR strain (P = 0.001, OR = 3.215, CI95% = 1.176–5.095), 82 (93.2%) were on mechanical ventilation (P = 0.04), 80 (90.9%) were with shock (P = 0.001, OR = 5.909, CI95% = 2.176–16.049), 68 (77.3%) had diabetes mellitus (P = 0.03), in 66 (75.0%) hemotransfusion was used (P = 0.03), 66 (75.0%) were with renal dysfunction (P = 0.0046), 59 (67.0%) had SOFA score > =13 (P = 0.032, RR = 12.00) and 57(64.8%) had primary type of bacteremia (P = 0.001).
High resistance of E. coli to aminopenicillins without and with beta-lactamases inhibitor, gentamicin, cefotaxim, ciprofloxacin and no resistance to carbapenems was estimated. Stay in ICU > =7 days was associated with admission from emergency department, MDR and ESBL strain of E. coli, mechanical ventilation > =3 days, shock, SOFA score > =13. Mortality rate of E. coli bacteremia 71% is significantly increasing and associated with diabetes mellitus, primary type of bacteremia, MDR strain, mechanical ventilation, shock, renal dysfunction, hemotransfusion and SOFA score > =13.
P410 Incidence of ESKAPE pathogens and their antibiotic resistance in patients with invasive devices in the ICU of a public hospital
K Hernandez, T Lopez, D Saca, M Bello
Universidad Dr. Jose Matias Delgado, Santa tecla, El Salvador
The objective of this study is to determine the incidence of ESKAPE pathogens, their antimicrobial resistance and association with invasive devices in the ICU of a public hospital during its inaugural year. Worldwide, most ICU-infections are caused by ESKAPE pathogens, whose high rates of antibiotic resistance are an active threat to public health.
A retrospective, cross-sectional analytical study was conducted, including all patients admitted to this ICU during 2014. Statistical analysis was performed using SPSS 20.0, Graph Pad Prism 6, and Open Epi 3.01.
150 cases were evaluated. The average age in the non-infectious, ESKAPE and non-ESKAPE cases was homogenous (Kruskal-Wallis Test, p = 0.053). 54% of cases were infectious. 13.3% of cases were ESKAPE cases. 46.4% (n = 26) of cultures isolated ESKAPE pathogens. Of these, Acinetobacter baumannii was the most common (50%). The most frequently prescribed antibiotics were ceftriaxone, imipenem and vancomycin, reporting resistance in 83%, 56.7% and 11.1% of the cultures respectively. 86.5% (n = 32) of the cases with pneumonia were associated with the use of endotracheal tube (ETT) (Xi2 Test, p = 0.0005). The cases with mechanical ventilation presented pneumonia 5.2 times more frequently than cases without it (OR 5.2, IC 95%, 1.9-14.4). 53% (n = 17) of the cases with pneumonia and ETT were caused by ESKAPE pathogens (p = 0.0711). 11.5% (n = 16) of the cases with UTI had a urinary catheter, and 2.8% were caused by an ESKAPE pathogen. The average ICU stay was 7.8 days, 4.9 days for the non-infectious cases, 7.3 days for the non-ESKAPE cases, and 19.5 days for the ESKAPE-cases (Kruskal-Wallis Test p < 0.0001). A moderate positive correlation between the days of mechanical ventilation and days of stay in ICU was established (Pearson r 0.59, p < 0.0001). The mortality rate was 45% in ESKAPE cases and 49% in non-ESKAPE cases. The infectious cases were lethal 3 times more frequently than the non-infectious cases (OR 3.052, IC 95%, 1.512-6.33).
Almost half of the cultures isolated ESKAPE pathogens. Ceftriaxone and Imipenem were most frequently prescribed antibiotics. Antibiograms reported high rates of resistance to these two antibiotics. All of the ESKAPE cases had at least two invasive devices. Pneumonia was more frequently diagnosed in patients with ETT. In average, the ESKAPE-cases stayed hospitalized 2.6 times longer than the non-ESKAPE-cases, and 4 times longer than the non-infectious-cases.
P411 Determinants of acinetobacter sepsis in critically ill patients: a comparative study
W Mahmood, K Hamed, N Al Badi, S AlThawadi, S Al Hosaini, N Salahuddin
King Faisal specialist hospital and research centre, Riyadh, Saudi Arabia
The incidence of Acinetobacter infections has steadily increased, and now lately, has become a major threat with the emergence of multidrug-resistant strains. Acinetobacter are notorious for their ability to spread amongst hospitalized patients. This study attempts to identify ICU care variables predictive of Acinetobacter sepsis.
In this case-control study, we extracted data from a prospectively collected ICU database on all patients admitted with a diagnosis of sepsis from 2010 to 2015. Identification data on all Acinetobacter isolates was obtained from the Section of Microbiology database. Patients with Acinetobacter sepsis were compared with control patients. The institutional Research Ethics Committee approved the protocol.
431 patients were studied, 43 (10%) developed Acinetobacter sepsis. Mean APACHE II score was 26 ± 7.7; median procalcitonin level was 3.9 (IQR 1.1, 18.4). Mean age was 52.5 ± 21.4 years with median ICU length of stay 6 (IQR 4.43) days. ICU mortality was 23% (99 patients) with mortality rate of patients with Acinetobacter sepsis at 60.5% (26 patients of 43). Patients who developed Acinetobacter sepsis had a mean SOFA score 14.1 ± 3.7 with 46.5% in septic shock, 9% organ donors, and 7% post-solid organ transplant. Most common site of isolation was the respiratory tract, 34.6%, followed by bloodstream/line sepsis, 30.8%, 32.5% had a single site infected. Median duration on mechanical ventilation was 15.3 (IQR 7, 15.3) days. On univariate regression analysis Acinetobacter sepsis was predicted by vasopressor dependence, OR 4.1 (95% CI 1.6,9.9, p =0.002), blood-stream infection, OR 6.3 (95% CI 3.2,12.4, p < 0.001), single site of initial sepsis OR 0.4 (95% CI 0.2, 0.9, p = 0.02), APACHE II score, OR 1.05 (95% CI 1.01, 1.1, p = 0.01), malignancy OR 6 (95% CI 2.2,15.7,p < 0.001) and appropriate empiric antibiotics OR 0.04 (95% CI 0.01,0.15, p < 0.001).On multivariate regression, appropriate empiric antibiotics OR 0.04 (95% CI 0.01,0.13, p < 0.001), vasopressor dependence, OR 3.1 (95% CI 1.07,9.2, p =0.03), blood-stream infection, OR 7.5(95% CI 3.2,17.4, p < 0.001), single site of initial sepsis OR 0.1 (95% CI 0.07, 0.4, p < 0.001) remained significant predictors of Acinetobacter sepsis.
Acinetobacter sepsis remains a frequent and hazardous ICU acquisition with a higher risk imposed by continued vasoplegia and septicemia and protective effects from appropriate initial antibiotic coverage and limited sites involved.
P412 Acute respiratory distress syndrome in patients with pneumococcal community-acquired pneumonia
CC Cilloniz1, AC Ceccato1, GL Li Bassi1, MF Ferrer1, AG Gabarrus1, OR Ranzani1, AS San Jose1, CG Garcia Vidal1, JP Puig de la Bella Casa1, FB Blasi2, AT Torres1
1Hospital Clinic, Barcelona, Spain; 2Università degli Studi di Milano, IRCCS Fondazione Ca Granda Ospedale Maggiore Policlinico, Milan, Italy
Community-acquired pneumonia (CAP) by Streptococcus pneumoniae could result into acute respiratory distress syndrome (ARDS). In patients with severe pneumococcal CAP, we characterized prevalence, risk factors and clinical outcomes of ARDS.
We prospectively enrolled adult patients admitted into a pulmonary intensive care unit (ICU). Patients were clustered based on ARDS occurrence, according to the Berlin definition. Characteristics, risk factors and outcomes were compared between groups.
Among 6439 patients with CAP, 1307 (20%) had pneumococcal CAP; of those, 282 (23%) patients were admitted to the ICU and 115 required ventilatory support (70%, invasive mechanical ventilation and 30% non-invasive mechanical ventilation). Thirty-six out of 115 (31%) ventilated patients met the Berlin ARDS criteria. ARDS was mild, moderate and severe in 36, 44 and 20% of the cases, respectively. Multivariate analysis indicated that previous corticosteroid therapy decreased risk of ARDS (odds ratio (OR), 0.33; 95% confidence interval (95% CI), 0.11-0.94). Patients with ARDS presented less ventilation-free days (p = 0.047), higher ICU mortality (39% vs. 18%; p = 0.014) and higher in-hospital mortality (22% vs. 42%; p = 0.025). ARDS was an independent risk factor for ICU mortality (OR, 2.60; 95%CI, 1.04-6.53).
ARDS develops in a minor proportion of patients with pneumococcal CAP. Yet, ARDS highly increases mortality risks. Previous treatment with inhaled corticosteroids is the only ARDS protective factor.
P413 Ventilator-associated pneumonia: MDR Gram-negative bacteria and predictors of mortality
D Adukauskiene1, A Ciginskiene1, A Dambrauskiene2, R Simoliuniene3
1Hospital of Lithuanian University of Health Sciences, Kaunas, Lithuania; 2Hospital of Lithuanian University of Health Sciences, Kaunas, Lithuania; 3Lithuanian University of Health Sciences, Kaunas, Lithuania
The aim of study was to evaluate antimicrobial resistance of Gram-negative bacteria (GNB) as pathogens of ventilator-associated pneumonia (VAP) and to determinate predictors of in-hospital mortality.
Retrospective data analysis of patients treated in ICU with multidrug-resistant strains of GNB as pathogens of VAP during 2015 was carried out.
In 77 VAP pts 98 multidrug-resistant strains of GNB were revealed: 37 (37.8%) of A. baumannii, 16 (16.3%) of Klebsiella spp., 11(11.2%) of Enterobacter spp., 10 (10.2%) of P. aeruginosa and others 24 (24.5%) as S. marcescens, Morganella spp., Citrobacter spp., E. coli, Proteus spp. In 34 (34.7%) of GNB strains multidrug-resistance (MDR), in 63 (64.3%) extensive drug-resistance (XDR) and in 1 (1%) pandrug-resistance (PDR) was ascertained. MDR was found in 7 (63.6%) of Enterobacter spp. and 7 (70%) of P. aeruginosa (p < 0.001), XDR - in 36 (97.3%) of A. baumannii strains (p < 0.001). One (10%) of P. aeruginosa strains was found to be PDR. 37 (48%) pts with multidrug-resistant pathogens of VAP have died. Statistical significant differences of survivors vs nonsurvivors were found in means of hospitalisation days prior of VAP 53.8 (SD = 34) vs 29,1 (SD = 17), p = 0.001, neutrophils percent 81 (SD = 8.9) vs 85 (SD = 6.3), p = 0.045, and between proportions of internal disease 7 (33%) vs 14 (67%), p = 0.042, co-infection 13 (30%) vs 30 (70%), p = 0.001, shock 16 (36%) vs 28 (64%), p = 0.03, multiple organ dysfunction syndrome 17 (40%) vs 25 (60%), p = 0.039, inappropriate initial antimicrobial treatment 18 (40%) vs 27 (60%), p = 0.02. OR for in-hospital mortality was: 8.9 (95% OR CI 2.24; 33.72) for co-infection, 4.67 (95% OR CI 1.7; 12.6) for shock and 3.3 (95% OR CI 1.27; 8.59) for inappropriate initial antimicrobial treatment.
A. baumannii and Klebsiella spp. were found to be predominating multidrug-resistant pathogens of VAP. 1/3 of all multidrug-resistant GNB of VAP were MDR and 3/5 were XDR. 2/3 of Enterobacter spp. and P. aeruginosa strains were found to be MDR. A. baumannii strain were found to be exclusively of XDR type. In-hospital mortality of VAP was 48%. Longer hospitalisation prior of VAP, neutrophilosis, internal disease, co-infection, shock, multiple organ dysfunction syndrome, inappropriate initial antimicrobial treatment were found to be associated with in-hospital mortality. Co-infection, shock and inappropriate initial antimicrobial treatment were found to be significant predictors for in-hospital mortality in ICU patients with multidrug resistant GNB in VAP.
P414 Predictors of mortality in KPC-Kp bloodstream infection in intensive care units in Italy
G Giuliano1, D Triunfio1, E Sozio1, E Taddei1, E Brogi1, F Sbrana2, A Ripoli2, G Bertolino1, C Tascini3, F Forfori1
1AOUP, Pisa, Italy; 2Fondazione Toscana Gabriele Monasterio, Pisa, Italy; 3First Division of Infectious Diseases, Cotugno Hospital, Napoli, Italy
Over the last decade, the prevalence of strains of Klebsiella Pneumoniae Carbapenemases (KPC) producing K. pneumoniae (Kp) has dramatically increased worldwide and has become a significant problem in terms of public health, especially in some countries.
In this retrospective observational study conducted in Intensive Care Units (ICU) of the the Italian teaching Hospital of Pisa, we recruited critically ill patients with a diagnosis of bloodstream infections (BSI) caused by KPC-Kp. 30-days mortality from the first positive blood culture, septic shock diagnosis, steroid therapy, SOFA, SAPS II, Charlson Score, antibiotics therapy, previous hospitalization were compared between Survivor and Non-Survivor groups.
We enrolled 42 patients admitted in ICU between January 2012 and December 2015. The overall 30 days mortality rate was 52,4%. A significantly higher rate was observed among patients with a diagnosis of septic shock at BSI onset, steroid therapy, higher SOFA and SAPS II score. Gentamicin used in combination therapy was associated with lower mortality, regardless of meropenem use. Furthermore, in colonized patients the digestive decontamination with oral Gentamicin decreased BSI mortality. Previous use of meropenem was associated with increased mortality. Additionally, the intravenous admistration of Fosfomicin resulted in a lower mortality rate. Charlson score and optimal empirical therapy seemed not to have a significant influence on survival.
See text for description
Survivor (n = 19)
Non survivor (n = 23)
3 Months previous hospitalization
P = 0.054
P = 0.024
P = 0.045
SOFA (day 1)
8.65 ± 3.37
11.9 ± 3.37
P = 0.015
SAPS II (day 1)
57.58 ± 17.70
67.59 ± 20.99
P = 0.034
3.05 ± 1.87
4.00 ± 1.87
Optimal empirical therapy
Previous carbapenems therapy
P = 0.081
Oral gentamicin decontamination
P = 0.093
P = 0.023
P = 0.066
Gentamicin associated with other antibiotics
P = 0.072
P415 Global burden of neonatal and childhood sepsis
C Fleischmann1, D Goldfarb2, P Schlattmann1, L Schlapbach3, N Kissoon4
1Jena University Hopital, Jena, Germany; 2University of British Columbia, Vancouver, Canada; 3University of Queensland, Brisbane, Australia; 4British Columbia Childrens Hospital, Vancouver, Canada
Neonates and children under 5 years are at major risk for sepsis, but knowledge on the global epidemiology of childhood sepsis is scarce. The aim of this study was to estimate the global burden of and mortality from sepsis in children and neonates based on available evidence from observational epidemiological studies.
Systematic review and meta-analysis. We searched 13 international databases for published and grey literature between 1979-2016, supplemented by hand search and expert consultation. Studies reporting on the incidence of sepsis in children (<20 y) defined according to the International Consensus Conference on Pediatric Sepsis Definitions , ACCP/SCCM consensus criteria [2,3] or related sepsis-relevant ICD-9/ICD-10 codes on a population level per 100 000 person-years or live births were included.
Of 1270 studies, 23 studies from 16 countries met the inclusion criteria. Sixteen were from high-income-countries, seven from middle-income-countries. Fifteen studies reported complete data and were included in the meta-analysis. We found an aggregate estimate of 48 [95% CI, 27-86] sepsis cases and 22 [95% CI, 14-33] severe sepsis cases per 100 000 child population in high-income-countries. Mortality ranged between 1-5% for sepsis and 9-20% for severe sepsis. The population-level estimate for neonatal sepsis was 2062 [95% CI, 1065-3957] per 100 000 live births with a mortality rate between 11-19% in middle- and high-income-countries. Extrapolating these figures on a global scale, we estimate 2.9 Mio. cases of neonatal sepsis with 319 000-551 000 neonates dying from or with sepsis.
Sepsis is a major contributor to neonatal and childhood mortality. Further comprehensive studies on sepsis epidemiology especially in low- and middle-income countries are needed, as well as effective measures to reduce the burden of sepsis in children globally.
(1) Goldstein et al. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005 Jan;6(1):2–8.
(2) Bone et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992;101:1644–1655.
(3) Levy et al. 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Crit Care Med 2003;31:1250–1256.
P416 Epidemiology of sepsis in Turkish intensive care units: a multicenter point- prevalance study.
N Baykara1, H Akalin2, M Kemal Arslantas3, And Sepsis Study Group4
1University of Kocaeli, Kocaeli, Turkey; 2Uludag University, Bursa, Turkey; 3Marmara University, Istanbul, Turkey; 4Turkish Society of Intensive Care Medicine, Istanbul, Turkey
The prevalance and mortality of sepsis in Turkey is largely unknown. Turkey is among the countries that have a high level of antibiotic resistance. Turkish Society of Intensive Care Medicine, Sepsis Study Group conducted a national, multicenter, point-prevalance study to determine the prevalence, causative microorganisms, and outcome of sepsis in Turkish ICUs.
A total of 132 ICUs from 94 hospitals participated the study. All patients (>18 yr old) present on the participating ICU or admitted for any length of time during a 24 hr period between 08:00 on Wednesday 27 January 2016 and 08:00 on Thursday 28 January 2016 were included the study. The International Sepsis Forum definitions for common sites of infection were used . The presence of SIRS, severe sepsis and septic shock was assessed and documented based on consensus criteria of the ACCP/SCCM (SEPSIS-I) . Data were also used to define septic shock according to the SEPSIS-III definitions . Demographics, severity of illness, comorbidities, microbiological data, therapies used, length of stay and outcome (dead or alive through 30 days) were recorded.
Of 1499 patients screened, 165 (11%) had sepsis, 260 (17.3%) had severe sepsis without shock, and 204 (13.6%) had septic shock. Mortality rates increased significantly with increasing severity of sepsis (31.3%, 55.8%, and 71.1%, for sepsis, severe sepsis and septic shock, respectively; p < 0.05). According to the SEPSIS-III definitions, 91 (10.5%) patients had septic shock and mortality rate for septic shock was 75.3%. The respiratory system was the most common site of infection, accounting for 62.8% of all infections, followed by the the bloodstream (14.9), and the urinary system (7%). Acinetobacter species were the most common isolated pathogen (34.5%), followed by Klebsiella species (16.7%) and Pseudomonas species (14.5%). While colistin was the last-line therapeutic drug used against multidrug-resistant Gram-negative pathogens, 5% of Klebsiella spp. isolates, 3.3% of Pseudomonas spp. isolates, and 2.4% of Acinetobacter spp. isolates were resistant to colistin.
This study found a high prevalance of sepsis and an unacceptable high mortality rate in Turkish ICUs.
1. Calandra T. Crit Care Med 2005;33:1538–1548.
2. Bone RC. Chest. 1992 Jun;101(6):1644–55.
3. Seymour CW.JAMA. 2016 Feb 23;315(8):762–74.
P417 Assessment of clinical criteria for sepsis in low and middle income countries
SG Gavrilovic1, MV Vukoja1, MH Hache2, RK Kashyap3, YD Dong3, OG Gajic3
1Istitute for Pulmonary Diseases of Vojvodina, Sremska Kamenica, Serbia; 2CEDIMAT, Santo Domingo, Dominican Republic; 3Mayo Clinic, Rochester, New York, United States
In 2016 The Third International Consensus Definitions Task Force defined sepsis as a life-threatening organ dysfunction due to a dysregulated host response to infection . Evaluation of new clinical criteria for this sepsis definition was not done so far in Low and Middle Income Countries (LMC). The aim of this study was to evaluate the prognostic ability of new and old clinical criteria for sepsis in LMCs.
This is a secondary analysis of CERTAIN (Checklist for Early Recognition and Treatmentof Acute Illness and Injury) study data from 15 intensive care units (ICU) from LMC. We included adult patients with discharge diagnosis of infection. Data on admission SOFA were collected prospectively. The presence of SIRS was determinedfrom prospectively collected APACHE II data on admission. Association with mortality was explored using univariate logistic regression.
Between October 2013 and July 2016, out of 1398 eligible patients, 131 patients (9.4%) were included in the study with both SIRS and SOFA and a discharge diagnosis of infection. There were 51 female (39%) and 80 male (61%) patients from 15 ICUs. Median SIRS was 2 (IQR 1-3) and median SOFA was 7 (IQR 4-9), 28 days mortality was 47.2%. The SOFA score was higher among non-survivors (7.84 +/- 3.8 vs. 6.42 +/-3.36, p = 0.03). SIRS score did not differ among survivors and non-survivors (1.7 +/- 1.2 vs. 2 +/- 1.3, p = 0.197).The SOFA score > =2 was predictivefor 28 days mortality (AUC 0.62, p = 0.03), while SIRS > = 2was not (AUC 0.56, p = 0.2).
In a sample of LMCs ICU patients with infection SOFA, but not SIRS sepsis criteria are predictive for 28 days mortality.
1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA (2016) 315:801–10.10.1001/jama.2016.0287
P418 Measuring and comparing sepsis outcomes between countries to explore the impact of heterogeneity: a case study on adult medical admissions in England and Brazil
O Ranzani1, M Shankar-Hari 2, D Harrison1, L Rabello3, K Rowan1, J Salluh3, M Soares3
1Intensive Care National Audit & Research Centre, London, United Kingdom; 2Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom; 3DOr Institute for Research and Education - IDOR, Rio De Janeiro, Brazil
We tested the hypothesis that differences in generic and sepsis-specific patient characteristics explain the observed differences in sepsis outcomes between countries .
We studied first ICU episode for adult medical patients with sepsis admitted during 2013 using national data sources from England (ICNARC Case Mix Programme) and Brazil (ORCHESTRA study). After harmonizing relevant variables, the datasets were merged.
Sepsis was defined as infection and > =1 organ dysfunction (OD) (> = 2 points) using a modified SOFA score to align with Sepsis-3 . The primary outcome was acute hospital mortality. We used multilevel logistic regression models to evaluate the impact of country (Brazil vs England) on hospital mortality, after adjustment for generic (age, sex, comorbidities, admission source, time to ICU admission) and sepsis-specific (infection site, OD type and first order interactions) characteristics. We report risk-adjusted mortality stratified by admission source, time in hospital prior to ICU admission, infection site, and decile of predicted risk of death (from our regression model).
Of medical ICU admissions, 30.7% (17,921/58,316) in England and 13.2% (4,505/34,150) in Brazil met the sepsis definition. The Brazil sepsis cohort was older and had greater prevalence of serious comorbidities and dependency when compared with England. Respiratory was the commonest infection site (England 61.8%, Brazil 50.7%). The commonest OD was respiratory in England (85.8%) and cardiovascular in Brazil (41.2%). Crude mortality was similar (England 39.3%, Brazil 41.4%). After adjusting for generic characteristics, Brazil had lower odds of mortality (OR 0.88 [0.75-1.02], p = 0.089). However, after adding sepsis-specific characteristics, Brazil had higher risk-adjusted mortality (OR = 1.22 [1.05-1.43]; p = 0.01; AUROC = 0.78; Brier Score = 0.18). We observed statistically significant interactions in the full model when stratifying by time in hospital prior to ICU admission, infection site and deciles of predicted risk of death.
We show for the first time that generic and sepsis-specific patient characteristics explain observed differences in sepsis outcomes between countries.
1. Shankar-Hari et al. Crit Care Med 2016; 44:2223–2230
2. Singer M et al. JAMA; 2016; 315: 801–10
P419 Long-term temperature control with the esophageal heat transfer device in non-cardiac-arrest patients
AM Markota, JF Fluher, DK Kogler, ZB Borovšak, AS Sinkovic
University Medical Centre Maribor, Maribor, Slovenia
Esophageal heat transfer device (Advanced Cooling Therapy, Chicago, Ill, USA) is a new temperature management device, which has mostly been used for temperature management in survivors of cardiac arrest . Our aim was to evaluate the effectiveness of the device in long-term temperature management in non-cardiac-arrest patients.
A retrospective study from January to November 2016 with inclusion criteria: the device used for >120h in non-cardiac arrest patients.
We included 3 males (age 67, 71 and 74 years) and 1 female (36 years). The duration of treatment with the device was 220, 192, 452 and 168h, respectively. Indications for temperature management were hyperthermia associated with sepsis (1 patient with meningitis, 2 with pneumonia and 1 with necrotizing fasciitis). Target temperature was determined by the attending physician (36-37°C in a patient with meningitis and one patient with pneumonia, 36.5-37.5°C for one patient with pneumonia, and 37-38°C in patient with fasciitis). Temperature was in target range for 81% of time, ±0.5°C outside target range for 11.6% of time, and > =0.6°C outside of target trange for 7.4%. The greatest temperature fluctuations (>2°C outside target temperature) were observed in the patient with fasciitis after return from operating theatre (the device was disconected from the chiller during surgery) (Fig. 14).
Esophageal heat transfer device can be used for effective long-term temperature control in non-cardiac arrest patients.
P420 Effects of adsorption of cytokines early in septic shock (the ‘ACESS-trial’) – results of the pilot study
I László1, N Öveges1, M Forgács1, T Kiss1, P Hankovszky1, P Palágyi1, A Bebes1, B Gubán1, I Földesi1, Á Araczki1, M Telkes1, Z Ondrik1, Z Helyes2, Á Kemény2, Z Molnár1
1University of Szeged, Szeged, Hungary; 2University of Pécs, Pécs, Hungary
Dysregulated systemic inflammatory response in septic shock often results an overwhelming “cytokine storm”, evolving into fulminant sepsis, with multiple organ dysfunction and early death. Attenuating the cytokine storm by adsorbing cytokines via hemoperfusion (CytoSorb) has pathophysiological rationale. Our aim was to investigate the effects of CytoSorb therapy on organ dysfunction and inflammatory response when started early (<48 h) in septic shock.
Patients fulfilling septic shock criteria were randomized into CytoSorb and Control groups. CytoSorb therapy lasted for 24 hours. Blood samples were taken to determine IL-1, IL-1ra, IL-6, IL-8, IL-10, TNF-α, PCT, CRP levels. At this stage of the study only PCT and CRP levels were analyzed. Organ dysfunction was evaluated by the Sequential Organ Failure Assessment (SOFA) score. Data were recorded on enrollment (T0) then at T12, T24, and T48 hours.
Within the first 2 years of the study 14 patients were randomized into CytoSorb (n = 7), and Control-groups (n = 7). Both SOFA scores and mortality risk showed significant decrease between T0 and T48 the CytoSorb group: T0 = 12.7 ± 3.5, T48 = 9.4 ± 6.2, p = 0.028; T0 = 55.4 ± 26.2, T48 = 34.0 ± 30.8%, p = 0.013. Dose of the required norepinephrine also showed a significant reduction by T48 as compared to T0 and T24 (T0 = 51.4 ± 53.0, T24 = 40.7 ± 45.4, T48 = 11.9 ± 18.1μg/min, p = 0.035). Regarding the inflammatory response PCT and CRP levels were grossly elevated at T0, but there was no difference between the CytoSorb-, and Control-groups within the first 48 hours.
According to our interim results CytoSorb therapy resulted in better SOFA scores, and also proved to be safe without significantly affecting PCT and CRP changes within the first 48 hours of septic shock. Based on the results of this current pilot study we are planning to design a prospective randomized multicenter trial.
ClinicalTrials.gov ID: NCT02288975
P421 Comparative anticoagulant effects of recombinant thrombomodulin, antithrombin, and unfractionated heparin – clinical implications
J Fareed1, Z Siddiqui1, P Aggarwal1, O Iqbal1, D Hoppensteadt1, M Lewis1, R Wasmund1, S Abro1, S Raghuvir1, K Tsuruta2
1Loyola University, Chicago, Illinois, United States; 2Asahi Kasei Pharma America Corporation, Waltham, Massachusetts, United States
Unfractionated heparin (UFH), antithrombin (AT), and recombinant thrombomodulin (RT) represent two distinct anticoagulant/antithrombotic agents with different targets in the hemostatic process to produce their therapeutic effects. Both of these agents are widely used in various hematologic indications in mono and poly therapeutic approaches. Currently, a recombinant version of thrombomodulin, ART-123 (Recomodulin) is undergoing clinical trials to validate its efficacy in sepsis-associated coagulopathy. Recomodulin is a novel, recombinant and soluble thrombomodulin, and is a human protein with both thrombin inhibiting and protein C stimulating activities. In comparison to both UFH and AT, this agent has relatively weaker anticoagulant activities related to bleeding risk at therapeutic concentrations of < = 1.25 ug/mL. Supratherapeutic concentrations of this agent may occur in some patients with renal dysfunction. The purpose of this study is to compare the anticoagulant and platelet modulatory effects of ART-123, UFH, and AT.
UFH of porcine origin was obtained from Medefil Inc. (Glendale Heights, IL) in powdered form with a specific activity of 175 U/mg. A working concentrations of this agent was made at 100 ug/mL in sterile saline. AT was commercially obtained from Baxter Healthcare Corporation (Deerfield, IL). A working concentration of AT was prepared at 100 U/mL in sterile saline. Recomodulin was commercially obtained and was manufactured by Asahi Kasei Pharma (Japan). A working concentration of Recomodulin at 100 ug/mL was prepared in sterile saline. The effect of Recomodulin, AT, and UFH on the glass activated clotting time and thromboelastographic (TEG) profile was measured at concentrations of 0-5 ug/mL. Global anticoagulant assays including PT, APTT, and TT were also measured in citrated whole blood and retrieved plasma. The effect of these drugs on agonist induced platelet aggregation (arachidonic acid, ADP, collagen, thrombin, and epinephrine) was measured in platelet rich plasma collected from healthy donors.
In comparison to both AT and UFH, Recomodulin did not produce any anticoagulant effects in either the TEG or the ACT tests at concentrations of 1.25 ug/mL. At higher concentrations of 2.5 and 5.0 ug/mL, the relative anticoagulant effects of Recomodulin were much weaker in comparison to both AT and UFH. In the TEG profile at 5.0 ug/mL, both the AT and UFH produced complete anticoagulation. However, Recomodulin did not produce a complete anticoagulation at 2.5 and 5.0 ug/mL. In the whole blood global clotting assays, all agents produced a concentration-dependent anticoagulant effect following the order UFH > AT > Recomodulin. In the platelet aggregation studies, while heparin produced a mild increase in the aggregation profile of some of the agonists, AT and Recomodulin did not produce any effects at concentrations of up to 10 ug/ml and 5 U/ml for all of the agonists except thrombin.
The circulating levels of Recomodulin for the management of sepsis-associated coagulopathy range from 0.5-1.5 ug/mL. The therapeutic levels of UFH for similar indications range from 1.5-5.0 ug/mL (0.25-1.0 U/mL), whereas the circulating AT levels may range from 1-2.5 U/mL. The results from this study suggest that Recomodulin is a much weaker anticoagulant in comparison to both UFH and AT and at therapeutic concentrations, it does not produce any measurable anticoagulant effects. At supratherapeutic concentrations of > 2.5 ug/mL, Recomodulin exhibits weaker anticoagulant effects which are unlikely to contribute to any hemostatic deficit resulting in potential bleeding complications.
P422 Safety of thrombomodulin (ART-123) in surgical patients with sepsis and suspected disseminated intravascular coagulation (S + DIC)
PS Barie1, D Fineberg2, A Radford2, K Tsuruta2
1Weill Cornell Medicine, New York, New York, United States; 2Asahi Kasei Pharma America, Waltham, Massachusetts, United States
We hypothesized that ART-123 is safe for therapy of S + DIC, particularly re: Bleeding risk. S + DIC occurs in 20%-35% of hospitalized patients with sepsis. Limited safety data exist for surgical patients receiving ART-123 for S + DIC despite substantial clinical use in Japan (>160,000 pts treated).
Retrospective review of a large Phase 2b, randomized, placebo-controlled trial of therapy with ART-123 to assess safety  in 741 treated pts. Data were analyzed for the presence and type (Table 4) of an operation within 30 d prior to randomization. On- treatment (during study drug admin or 4 d thereafter) serious major bleeding events [SMBEs] (any intracranial hemorrhage, any life-threatening bleeding, any bleeding investigator-classified as serious by the investigator, or any bleeding that required > 6 U red cell concentrates over two consecutive days, and 28-d mortality were compared. Χ2, p < 0.05.
226/741 (30.5%) were surgical patients (SP). Most (80%) operations were abdominal. Primary infection source is listed in Table 5. Among non-surgical (NS) patients, SMBEs occurred in 4.8% (12/252, ART-123 group; 3 fatal) vs. 4.2% (11/263, placebo group; 4 fatal) (p = ns). Among SP, SMBEs occurred in 5.9% (7/119, ART-123 group; 1 fatal) vs. 5.6% (6/107, placebo group, 0 fatal) (p = ns). 28-day mortality among SP was 21.0% (25/119, ART-123) vs. 29.0% (31/107, placebo) (p = ns); this compares with NS mortality of 16.3% (41/252, ART-123) vs. 18.6% (49/263, placebo) (p = ns).
Similar rates of SMBEs exist between ART-123- and placebo-treated SP; ART-123 appears to be safe regarding bleeding risk after surgery. Further research is needed for SP with S + DIC to evaluate the effect of ART-123 on outcomes.
See text for description
ART-123 n = 119
Placebo n = 107
Total n = 226
See text for description
SP n = 226
NS n = 515
P423 Vasopressin + Norepinephrine in septic shock: effects on renal function – a retrospective analysis
A Casazza1, A Vilardo2, E Bellazzi1, R Boschi1, D Ciprandi1, C Gigliuto1, R Preda1, R Vanzino1, M Vetere1, L Carnevale1
1ASST di Pavia, Vigevano, Italy; 2Scuola di Specialità Anestesia e Rianimazione, Università Degli Studi, Pavia, Italy
Norepinephrine (N) is the first-line vasopressor in septic shock, Vasopressin (V) is used in catecholamine-resistant shock to reach intended MAP, however the dosage of N at which V should be added is unknown and outcome effects are debated. New data suggested that low dose V is effective in intermediate severity septic shock  and has positive effects on renal function .
We retrospectively analysed all septic shock patients admitted to our general ICU from 09/2013 to 08/2016 and treated with N or association V + N. We identified 3 different groups. In N group (low severity), patients received only N < 0.4mcg/kg/min to reach MAP > 65mmhg; in VN-L group (intermediate severity), V at a dosage of 0.02-0.03 U/min was added to N at a dosage < =0.4 mcg/kg/min; in VN-H group (high severity), despite V infusion, N needed to be titrated > 0.4 mcg/kg/min. We analysed SOFA score at admission, mortality rate and need for RRT during ICU stay, vasoactive drugs infusion length, urine output and progression of AKI by RIFLE classification during the first week of ICU stay. Patients with end stage kidney disease at admission were ruled out. Data were analysed by Anova and Fisher’s exact tests.
We enrolled 39 patients; 16 in N group, 16 in VN-L and 7 in VN-H. SOFA at baseline was 10 in N patients, 12 in VN-L and 14 in VN-H (p < 0.05). Overall mortality was 39.5%: VN-L patients showed lower mortality rate (31.1%) than VN-H (71.4%) and N group (37.5%) (p 0.38). Need for RRT was 18.8% in N and VN-L series and 57.1% in VN-H. Urine output was higher in VN-L patients than N and VN-H ones without statistical significance (p 0.35). In N group, 3 patients without AKI at baseline didn’t develop renal failure; 9 patients (69.2%), 4 in R, 3 in I and 2 in F RIFLE categories, improved their renal function. In VN-L group, only 1 patient without AKI were admitted and didn’t worse his renal function; 12 patients (80%), 5 R, 4 I and 3 F class, improved renal function. In VN-H series, 1 patient admitted without AKI didn’t develop renal failure, and 1 I category patient (16.7%) improved, but all F patients worsened to L (p 0.40). Vasopressors infusion mean length was 5,6 days in N, 4.3 in VN-L and 10.4 in VN-H series (p < 0.05).
Although, in our analysis, several data do not reach statistical significance, the association V + N, in the intermediate severity group, seems to have favorable effects on the urinary flow, on the progression of AKI and on vasoactive drugs infusion length.
 Mehta et al, Crit Care 2013 Jun 20; 17(3).R117
 Gordon et al, JAMA.2016;316(5):509–518
P424 Pentaglobin administration provides feature of trained immunity against multidrug-resistant (MDR) gram-negative bacteria
E Kyriazopoulou, A Pistiki, C Routsi, I Tsangaris, E Giamarellos-Bourboulis
National and Kapodistrian University of Athens, Medical School, Athens, Greece
Recent data of the Hellenic Sepsis Group showed that treatment of severe infections by the IgM-enriched preparation Pentaglobin delayed the advent of breakthrough bacteremia suggesting a probable trained immune effect . We investigated if Pentaglobin can elicit such trained immune responses.
Interleukin(IL)-10 were selectively measured in serial serum samples from five patients with ventilator-associated pneumonia of a prospective cohort  who received Pentaglobin at the discretion of the attending physicians. Fresh peripheral blood mononuclear cells (PBMCs) were isolated from six healthy volunteers and pre-treated for 24 hours with medium or Pentaglobin so that final IgM concentration was 50mg/dl. After washing, PBMCs were stimulated for 24 hours with heat-killed 5log10-growth isolates of Klebsiella pneumoniae producing-carbapenemase (KPC) and multidrug-resistant Pseudomonas aeruginosa (MDRPA). Isolates were selected from those infecting already described Greek patients; isolates were kept frozen and thawed . Tumour necrosis factor (TNF) alpha was measured in PBMC supernatants by an enzyme immnosorbent assay.
Mean IL-10 at baseline was 58.5 +/- 46 pg/ml and on day 3 36.9 +/- 23.1 pg/ml (p: 0.043). IgM pre-treatment did not affect TNFalpha production. After stimulation with MDRPA and KPC TNFalpha was significantly higher from IgM pre-treated PBMCs (Fig. 15).
Pentaglobin pre-treatment leads to enhanced TNFα responses after re-stimulation with resistant Gram-negative hospital-acquired pathogens simulating enhanced host responses. This corroborates with the decrease of circulating IL-10 shown in patients and explains the protection from breakthrough bacteremia seen in our recent clinical study .
1.Giamarellos-Bourboulis EJ, et al. CMI 2016; 22: 499
P425 Long-term survival benefit of pentaglobin for severe infections by multidrug-resistant (mdr) gram-negative bacteria
E Kyriazopoulou1, I Tsangaris1, C Routsi1, I Pnevmatikos2, G Vlachogiannis3, E Antoniadou4, K Mandragos5, A Armaganidis1, E Giamarellos-Bourboulis1
1National and Kapodistrian University of Athens, Medical School, Athens, Greece; 2University of Thrace, Alexandroupolis, Greece; 3Aghios Dimitrios General Hospital, Thessaloniki, Greece; 4G.Gennimatas General Hospital, Thessaloniki, Greece; 5Korgialeneion Benakeion Hospital, Athens, Greece
In a recent publication, 100 patients with severe infections by MDR Gram-negative bacteria were treated for five days with one IgM-enriched immunoglobulin preparation (IgGAM, Pentaglobin); they had favorable 28-day outcomes compared to 100 well-matched comparators for all infection variables . We re-analyzed regarding long-term outcomes.
Patients were sub-grouped by SOFA score; survival on day 90 was compared by the log-rank test. Serial procalcitonin (PCT) measurements were available for 22 IgGAM-treated patients and 35 comparators and compared by the Mann-Whitney U test.
In the subgroup with SOFA more than 10, survival until day 90 was prolonged with IgGAM (median 27 vs 8 days, Fig. 16). Although a trend for prolonged survival was shown with SOFA 10 or less (median 42 vs 27 days) this was not statistically significant. PCT started to decrease in the IgGAM group by day 5; median PCT of the IgGAM group was 0.17 (0.02-0.72) ng/ml and of the comparators 0.67 (0.24-13.28) ng/ml (p: 0.012).
IgGAM treatment achieved better 90-day outcomes among the more severe patients. This was associated with decrease of PCT.
P426 Medical application content quality metrics: a cross-sectional survey of current applications used to aid the management of sepsis
P Allan1, R Oehmen2, J Luo1, C Ellis 1, P Latham3, J Newman 4
1Rockingham General Hospital, Cooloongup, Australia; 2University of Notre Dame, Fremantle, Australia; 3Mackay Hospital, Mackay, Australia; 4Queen Alexandra Hospital, Portsmouth, United Kingdom
The use of mobile applications (apps) by healthcare practitioners is increasing globally . While this has the potential to improve clinical knowledge translation, it also represents a potential source of medical risk due to a lack of both regulation and validation. In this study, we attempt to assess the quality of currently available apps relating to the management of sepsis.
Between the 15th and 19th of April, 2016 a detailed search was completed of all apps available on the two largest global app stores relating to sepsis. Search terms ‘sepsis’, ‘septic’ and ‘septic shock’ were used. Matching apps were assessed against set inclusion criteria such as ‘English language only’, “not a game”. Apps meeting these criteria were then purchased and reviewed for further metrics including intended audience, and content design. Apps not intended for medical practitioners and those not relating to the management of sepsis were further excluded. Remaining apps underwent a detailed review of content including the representation of international sepsis guideline information, author metrics, references, legal disclaimers as well as update and review processes.
Search terms returned 236 unique apps. 19 apps passed all barrier conditions for final review. Of these, 15 were information references only and did not modify management information based on user entered patient data. Of the 4 apps that did, only 2 offered a commitment to maintaining privacy. Reference apps were typically not specific to sepsis management but rather covered a broad range of diseases. 5 apps were electronic versions of published medical textbooks. Instances of information conflicting with guidelines was common. Only 12 apps included references. Periodical updates were evident in the majority of surveyed apps, but only 8 apps had been updated within 12 months. Legal disclaimers outlining liability were observed in only 8 of 19 applications. No application explicitly mentioned the presence or absence of any conflicts of interest.
The quality of surveyed medical apps concerning sepsis management varied greatly. The potential for clinical risk is high due to the lack of regulation governing currently available medical apps. The development of designer, consumer and market-based processes to regulate medical app content is important as this technology is increasingly integrated into modern clinical practice.
1.Wyatt, J. C. et al. Clin Med. (Northfield. II). 15, 519–521 (2015)
P427 Simulating sepsis: can it improve delivery of the sepsis six in the emergency department?
C Pritchett, D Pandya, A Cripps, S Harris, M Jadav, R Langford
Royal Cornwall Hospital, Truro, United Kingdom
In this study we assessed the effectiveness of our sepsis simulation based education (SBE) course using the Kirkpatrick learning evaluation model  in a cohort of Emergency Department (ED) physicians. Few simulation articles have demonstrated change in participant’s behaviour (Kirkpatrick level 3) . Such evidence demonstrates translation of learning into practice. Delivery of the ‘sepsis 6’ within 1 hour reduces mortality and morbidity of septic patients . At the Royal Cornwall Hospital we have instigated multi-disciplinary sepsis study days to improve care of septic patients.
8 ED Drs and 3 nurses received training in sepsis management and human factors followed by 2 in-situ simulated sepsis scenarios in the ED. Data was collected relating to Kirkpatrick level. Level 1 data assessed participant views on delivery, content and relevance using Likert scales. Improvement of knowledge was assessed using a questionnaire before & after the course. To assess behaviour change of the 8 physicians in attendance, time to completion of each of the sepsis 6 steps was collected for all septic patients they cared for 2 weeks before and 2 weeks after the course. Data was obtained from the ED management tool ‘Oceano’, and patient electronic records.
Kirkpatrick level 1: Overall satisfaction was high with averages of 4.5/5 for the sepsis seminar & simulation and 4.3/5 for the human factors seminar. Kirkpatrick level 2: Knowledge of sepsis improved from pre-to post test scores by an average of 4.8 marks out of 20. Kirkpatrick level 3: The 8 ED physicians who attended training treated 37 septic patients 2 weeks prior to training and 15 septic patients 2 weeks following training. Documented delivery of all sepsis 6 components improved from 32% to 53% (p = 0.17). Documented delivery of all 6 components within 1 hour improved from 8% to 33% (p = 0.0001).
Our course has demonstrated that participants enjoy and gain knowledge in sepsis and human factors in the context of SBE. Importantly it has demonstrated a statistically significant improvement of sepsis 6 delivery within 1 hour.
1. Kirkpatrick et al. Evaluating Training Programmes: the four levels. 3rd edition. San Francisco (CA): Berrett-Koehler; 2006
2. Boet S et al. Transfer of learning and patient outcome in simulated crisis resource management: A systematic review. Can J Anesth (2014) 61: 571–582
3. Dellinger RP et al, Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580–637
P428 Quick sequential organ failure assessment compared to systemic inflammatory response syndrome for predicting sepsis in emergency department
B Ko, H Park
Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, South Korea
It is unclear whether qSOFA also has prognostic value for organ failure in patients with suspected infection. The aim of this study was to determine the prognostic value of qSOFA compared to systemic inflammatory response syndrome (SIRS) for predicting organ failure in patients with suspected infection in emergency department (ED).
We retrospectively reviewed the medical records of 3234 patients with suspected infection in ED of a university-affiliated hospital during a 10-year period. We analyzed the ability of qSOFA compared to SIRS for predicting organ failure development (defined as an increase in the SOFA score of 2 point or more) in patients admitted at ED using area under receiver operating characteristic (AUROC) curve.
A total of 1009 patients with suspected infection finally included in the study, 627 (62.1%) experienced organ failure development within 24 hours after ED admission. The predictive validity of qSOFA for organ failure was higher than that of SIRS (AUROC = 0.814; 95% CI: 0.72-0.91 vs. AUROC = 0.662; 95% CI: 0.58-0.75; p = 0.02). The qSOFA was also superior to SIRS for predicting in-hospital mortality (AUROC = 0.733; 95% CI: 0.64-0.83 vs. AUROC = 0.599; 95% CI: 0.51-0.69; p = 0.04). When qSOFA score was equal to or greater than 1, its sensitivity and specificity for predicting organ failure were 75% and 82%, respectively.
qSOFA can predict the occurrence of organ failure in patients with suspected infection. It has a superior predicting ability than SIRS. Further prospective study about the optimal cutoff value of qSOFA for predicting organ failure is warranted.
1. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101(6):1644–1655.
2. Sprung CL, Sakr Y, Vincent JL, et al. An evaluation of systemic inflammatory response syndrome signs in the Sepsis Occurrence In Acutely Ill Patients (SOAP) study. Intensive Care Med. 2006;32(3):421–427.
P429 Influenza-associated risk factors for ICU admission and mortality
CM Beumer1, R Koch1, D V Beuningen1, AM Oudelashof2, FL Vd Veerdonk1, E Kolwijck1, JG VanderHoeven1, DC Bergmans2, C Hoedemaekers 1
1UMC Nijmegen, Nijmegen, Netherlands; 2Maastricht University Medical Centre, Maastricht, Netherlands
Influenza is associated with high morbidity and mortality rates worldwide. The severity of influenza infections is increasing over the last years. In this study we aimed to identify risk factors for ICU admission and mortality for influenza patients during the 2015-2016 epidemic in The Netherlands.
We performed a retrospective cohort study in influenza patients who were hospitalized in two university hospitals during the 2015-2016 influenza epidemic. Cases were identified using databases of the microbiology departments at both medical centers. Patients admitted to the hospital with clinical symptoms due to an acute infection with Influenza A or B were included in this study. Virus samples were obtained from nose/throat swab, sputum collection or bronchoalveolar lavage. A laboratory confirmed novel influenza infection was defined as a positive polymerase chain reaction, immunofluorescence assay or simple culture for either influenza A or B. In patients where a rapid influenza test was initially used, one of the above laboratory techniques subsequently had to be positive before a patient could be included in the study as a case.
We identified 200 cases with influenza type A or B admitted to one of the index hospitals. Data of 1 patient was of poor quality and excluded from further analysis. Overall mortality was 9%. 45 patients (23%) of the patients were admitted to the ICU, either primarily or later during the disease. Risk factors for ICU admission were smoking (p = 0.01), a history of OSAS/CSAS (p = 0.03) and myocardial infarction (p = 0.007). The development of renal failure and secondary (pulmonary) infections were also associated with ICU admission (P < 0.001). 17 of the 45 (38%) patients admitted to the ICU died during admission. Risk factors for ICU mortality included diabetes (p = 0.04) and renal failure before and during ICU admission (p = 0.01). In 25 out of 45 patients (55.6%) a secondary pulmonary infection developed. The most common bacterial pathogens included staphylococcus aureus (11.1%) and streptococcus pneumoniae (6.7%). Among the secondary fungal infections, Aspergillus fumigatus was most common (17.8%), followed by pneumocystis jirovecii (6.7%). Patients with a secondary infection received oseltamivir more often (100% vs. 65.0%, p = 0.002). No association was observed between other immunosuppressive drugs and the development secondary pulmonary infections.
Development of secondary pulmonary infections is a frequent complication in patients with influenza and associated with an increased risk of ICU admission. Early identification and treatment of these patients may prevent ICU admission.
P430 Infection rate during therapeutic hypothermia in children
JB Brandt, J Golej, G Burda, G Mostafa, A Schneider, R Vargha, M Hermon
Medical University of Vienna, Vienna, Austria
Several studies showed neuroprotective and immunomodulatory mechanisms of therapeutic hypothermia (TH). TH negatively affects leucocyte migration and synthesis of cytokines and is therefore thought to enhance infection rate due to impaired immunosurveillance. However, data for TH in children is limited. Therefore, we analyzed incidence of infections and outcome of children treated with TH (TH-group) and compared them to normothermic patients (NT- control group).
This study was performed as a retrospective case control study (from 2000 to 2012). All medical records and laboratory files of patients (newborns and children until 18 years of age), receiving TH for 24 to 72 hours, were screened and compared to a NT-group (historic control group with conventional treatment). Both groups were matched according to diagnosis and age. Data was analyzed from the day of admission to ICU until day 6. Indications for TH-initiation were cardiac arrest, peripartal asphyxia, traumatic brain injury, ischemic stroke, cerebral haemorrhage, -edema or –seizures, as well as acute liver failure. Patients with evident infection, medical history of an immunodeficiency disorder and / or an immunosuppressive therapy, before onset of TH, were excluded. TH (32-34°C) was induced by using a non-invasive cooling device. After 72 hours rewarming was started (0.2-0.3°C/hour).
108 patients were included (TH-group n = 27, NT-group n = 81). Survival rate showed no significant difference (81% of TH and 78% of NT, p = 0.996). CRP elevation (>1.2 mg/dL) was earlier in the TH-group and showed a significant difference on day 6 (4.93 mg/dL) to NT-group (2.36 mg/dL, p = 0.007). 22,2% of patients in the TH-group had culture proven infections in comparison to 4% within the NT-group. Five patients in the NT-group showed only clinical signs of infection. Pneumonia was the most commonly culture proven infection within both groups (TH 14.8% and NT 6.2%).
We report that therapeutic hypothermia did not significantly alter overall survival and length of hospital stay in our pediatric center. Similar to previous observations , our results showed a significant increase of CRP levels in TH patients as compared to NT controls, and had more culture proven infections. This data underlines the necessity of continuous monitoring for possible infectious complications when TH is used in pediatric intensive care setting.
1. Okumus, N. et al.: Am. J. Perinatol. 32: 667–674 (2015)
P431 The role of the ICU in the spread of Acinetobacter baumannii through the hospital
P Levin1, C Broyer1, M Assous1, Y Wiener-Well1, M Dahan1, S Benenson2, E Ben-Chetrit1
1Shaare Zedek Medical Center, Jerusalem, Israel; 2Hadassah Hospital, Jerusalem, Israel
Nosocomial acquisition of multidrug resistant Acinetobacter baumannii in the ICU is common. Despite a high fatality rate, over 50% of ICU Acinetobacter carriers are discharged alive from ICU to hospital wards where they continue to represent a source for cross transmission. We describe an intervention to terminate an ICU Acinetobacter outbreak and investigate the effect on hospital wide Acinetobacter prevalence.
ICU Acinetobacter incidence and prevalence were detected from surveillance and clinical cultures. Hospital prevalence was determined from clinical cultures. The Acinetobacter control intervention included unit closure with intense environmental cleaning, a hand hygiene intervention, improved cleaning protocols and the use of virtual walls. Data for the year preceding and following the intervention were compared for (1) ICU admission prevalence and ICU acquisition of Acinetobacter, (2) hospital prevalence of Acinetobacter and (3) Colistin use.
In the year prior to the intervention (6/2014 – 5/2015), Acinetobacter was isolated during 65/513 (13%) ICU admissions. Acinetobacter was isolated within 48 hours of ICU admission on 32/65 (49%) occasions and acquired in the ICU thereafter on 33/65 (51%) occasions. Acinetobacter positive patients were discharged alive to the wards on 48/65 (74%) occasions. In the year following the intervention (6/2015-5/2016) Acinetobacter was cultured during 4/516 (0.8%) ICU admissions (p < 0.001 vs preintervention), only one patient acquired Acinetobacter in the ICU and one Acinetobacter positive patient was discharged alive to the ward. In the hospital at large, Acinetobacter prevalence decreased by 58% from 185/39421 (0.5%) to 107/40292 (0.3%) admissions (p < 0.001). ICU and non-ICU hospital Colistin use (in defined daily doses/1000 patient days) decreased from 250 to 68 (p < 0.001) and 21 to 12 (p < 0.001) respectively.
The ICU intervention decreased ICU acquisition of Acinetobacter and ICU discharge of Acinetobacter positive patients to the wards and was associated with a decrease in hospital prevalence of Acinetobacter. Numerically, the decrease in hospital prevalence (from 185 to 107 patients) exceeded the decrease in ICU discharge of Acinetobacter patients (from 48 to 1). This could suggest that decreased ICU discharge of Acinetobacter positive patients leads to a lower Acinetobacter load in the wards and thus decreased transmission in the wards. The decreased load of Acinetobacter also facilitated a decrease in Colistin use. In conclusion, control of an ICU Acinetobacter outbreak had positive ramifications throughout the hospital.
P432 Observational study of central venous catheter care and reasons for removal
A Faux1, R Sherazi1, A Sethi2, S Saha1
1Queens Hospital, Essex, United Kingdom; 2King George Hospital, Ilford, United Kingdom
Vascular catheters are a ubiquitous tool in the critical care setting; however their use does not come without risks. Potentially one of the most serious and preventable complications is catheter-related blood stream infection (CR-BSI). The aim of this study was to examine the reasons why central venous catheters (CVC) are removed, whether there is clinical improvement following removal, and see how this relates to rates of CR-BSI.
We retrospectively studied the insertion, care, and reason for removal of central venous catheters across a single NHS trust. This data was then matched with the corresponding biochemical and microbiological results for each patient. Suspected CR-BSI was defined as clinical evidence of sepsis and with no apparent source of septicaemia except catheter tip colonization. Confirmed CR-BSI was subsequently defined by colonisation of a catheter tip with the same micro-organism grown from a peripheral blood culture. A routine change of CVC or arterial catheter was defined as replacement without evidence of sepsis or problems with the functioning of the catheter.
A total of 87 CVCs were studied with an average duration of insertion of 5.5 days. The most common reason for removal was absence of indication (28.7%). 17 out of 87 (19.5%) of CVCs were removed due to suspicion of CR-BSI, and of these only 1 was confirmed (Table 6). We further examined the cultured catheters for evidence of biochemical improvement following removal (Table 7). Of those who experienced improvement of inflammatory markers following CVC removal, we found no difference in mean duration of insertion, and similarly they were no more likely to have colonised CVCs than patients who did not experience improvement of their inflammatory markers (25% vs 29%).
In the NHS trust studied we found that 16.1% of central venous catheters were routinely changed after an average of 7.1 days without obvious indication other than to prevent catheter-related infection. Although some of these lines were colonised when cultured, we did not find any biochemical benefit of removing them routinely. This is consistent with evidence from randomised trials showing that routine replacement does not reduce rates of catheter-related bloodstream infection compared with changing them when clinically indicated .
 Eyer S, Brummitt C, Crossley K, Siegel R, Cerra F. Catheter related sepsis: prospective, randomized study of three methods of long-term catheter maintenance. Critical Care Medicine. 1990;18:1073–9.
See text for description
No longer indicated
Mean duration (days)
Positive peripheral culture
See text for description
WCC + CRP 48-hours post CVC removal
Mean duration (days)
P433 Elimination of LPS and cytokines from blood of septic patients with LPS-adsorber
M Kiselevskiy1, E Gromova1, S Loginov2, I Tchikileva1, Y Dolzhikova1, N Krotenko 2, R Vlasenko1, N Anisimova1
1Russian Cancer Research Center, Moscow, Russia; 2SP Botkin Hospital, Moscow, Russia
LPS-adsorption by Alteco® devices allows eliminating from blood endotoxin, inflammatory mediators and activated leucocytes .
20 patients with septic shock were enrolled ingram-negative the study. The values of IL-4, IL-6, IL-8, IL-10, IL-18 in serum and washout from LPS-adsorber were measured by ELISA. Concentrations of LPS were measured by modified micro gel clot test.
LPS level in blood significantly reduced after the hemoperfusion procedure (equally or more than twofold) in 50% of the patients with its initially high level (Fig. 17). Significant reduction of serum LPS level required from 2 to 6 hemoperfusion procedures. We did not detect any changes in the patients with initially low level of LPS. IL-6 and IL-8 showed the most prominent concentration changes among the cytokines under the study. Their level dropped down from 2 to 10 times after the procedure in many of the patients with initially high level of the cytokines. Number of functionally active leucocytes with high phagocytic activity and enhanced expression of CD11c adhesion molecules decreased after the hemoperfusion procedure in the patients. Substantial part of the leucocytes adhered on the Alteco hemofilter plates (Fig. 18).
Hemoperfusion procedure allows eliminating from the blood not only LPS, but excess inflammatory mediators as well. Adhesion of activated neutrophils on the Alteco hemofilter allows eliminating from the bloodstream of septic patients the most reactogenic phagocytes releasing cytotoxic free radicals.
P434 Early appropriate empirical therapy is associated with increased survival rate in patients with abdominal sepsis
S Spadaro, A Fogagnolo, F Remelli, V Alvisi, A Romanello, E Marangoni, C Volta
Sant’Anna Hospital, Ferrara, Italy
Sepsis is the most common cause of death by infection. In particular, abdominal sepsis is characterized by the highest death ratio and a complicate management, because of the high variability of microorganisms involved and the growing problem of antibiotic resistance. Therefore, the aim of this study is to identify potentially modifiable risk factor of death in patients with abdominal sepsis.
This is a prospective-observational study conducted in ICU at Sant’Anna Hospital, Ferrara. All patients >18 years admitted with the diagnosis of abdominal sepsis, according to 2016 sepsis criteria, were enrolled. We collected clinical and demographic data for each patient. Moreover, we recorded laboratory and blood gas analysis data microbiological investigations, anti-infective treatment (antimicrobial therapy/source control) and fluid balance. Primary outcome was 90-days mortality.
Thirty patients were enrolled. Clinical and demographic variable are shown in Fig. 19. The 61% of isolated microorganisms were multiresistant (MDR). Mortality in patients affected by MDR bacteria was not increase (36% vs 35%; p = 0.91). However, an appropriate empirical antibiotic therapy in the first 12 hours was found to be associated with a decreased mortality from 70% to 12% (p = 0.01). Moreover, positive fluid balances for more than 72 hours were more frequent in non-survivor patients (47% vs 18% p = 0.04).
In our population, MDR bacteria were highly represented. However, not the resistance itself, but the failure of an appropriate early empirical therapy was strongly associated with increased mortality; therefore, the knowledge of the local epidemiology of microorganisms and of their drug-resistance is crucial. Moreover, the inability to get a null or negative fluid balance after the first 72 hours in the ICU is a risk factor for 90-days mortality.
P435 Addressing empirical antimicrobial therapy in bacterial pneumonia: a new heterogeneous scoring system
A Degrassi, F Mearelli, C Casarsa, N Fiotti, G Biolo
University of Trieste, Trieste, Italy
Health care associated pneumonia (HCAP) ability to identify pneumonia sustained by multi drug resistant pathogens is controversial . We sought to provide a new scoring system addressing the empirical antimicrobial therapy based on the correct identification of resistant pathogens in patients with pneumonia.
In this prospective observational study, we considered 93 adult patients with microbiological confirmation of pneumonia. We looked for the prevalence of Community-Acquired Pneumonia-Drug-Resistant Pathogens (CAP-DRP), among patients classified and treated as having CAP or HCAP. The primary goal was to assess whether the appropriateness of initial empiric therapy would affect the short term mortality and if we could improve it with a new scoring system.
Results: We considered 51 CAP and 42 HCAP patients with microbiological confirmation of infection. Receiving inappropriate empirical antimicrobial therapy was an independent risk factor for 30 days’ mortality (P = 0.018, OR 5.32 [95%C.I. 1.26-22.73]). Among 76 bacteria-sustained pneumonias, 22.3% had CAP-DRP. After applying HCAP definition, we found 4.7% of CAP-DRP among CAP, and 44% among HCAP. Previous hospitalization, residence in nursing home or long-term facilities, non-ambulatory status and usage of PPI/antiH2 were predictors of CAP-DRP pneumoniae and were turned into an equation that identifies them with AUC of 0.847 [95%C.I. 0.732-0.962], performing better than HCAP model (AUC = 0.780, 95%C.I. 0.663-0.898). Figure 20. DRP score: solid line, HCAP model: dashed line. DRP score = (hospitalization*4.743) + (nursing home residence*4.31) + (non-ambulatory status*-2.444) + (use of PPI/antiH2*-2.361). A score higher than 0.933 is a predictor of CAP-DRP.
Conclusions: HCAP-addressed empirical therapy leads to overtreatment and undertreatment of a considerable percentage of patients with pneumonia. Among them, the score system we propose may help to choose the most appropriate empiric antimicrobial therapy, aiming at reducing inappropriate initial therapy and its associated mortality.
P436 Implementation of strategies of antimicrobial stewardship program in an intensive care unit in a university hospital in Chile
M Cariqueo, C Luengo, R Galvez, C Romero, R Cornejo, O Llanos, N Estuardo, P Alarcon
Hospital Clínico Universidad de Chile, Santiago, Chile
Antimicrobials are the 51% of the drugs used in intensive care units (ICUs)  and antimicrobial resistance has increased dramatically in recent years. Antimicrobial stewardship (AMS) programs aims to establish strategies to improve the use of antimicrobial and reduce resistance, adverse effects, Clostridium difficile infections and cost . International guideline proposes restrictive, persuasive and structural strategies. In Chile, the feasibility of these programs are not totally studied. We showed a process of implementation AMS programs in our ICU.
We conducted a 3 steps process of implementation of AMS program. We reviewed the literature to identify AMS strategies published from 2010 to 2016, inclusion criteria were studies in adult patients, high complexity hospitals or ICU, and have description of the strategies in their results. A local survey was applied to 8 health care professional to evaluate the feasibility to implement the strategies found, this survey consists of positives, neutral and negative answers and if the strategy counts with a half of positive answers we considered a possible implementation. A team with clinical pharmacist, intensivist and infectious diseases physicians worked on the set to develop the optimal way to implement these strategies in our ICU.
We found 362 studies about AMS program, in which 49 included 21 strategies in ICUs. Strategies were classified in restrictive, persuasive and structural. In our unit 9 of those are already implemented. According to local survey 7 strategies were feasible to implement (Fig. 21). Implementation was carried out through two processes: Medical record optimization and local guideline of antimicrobial treatment.
With a baseline of 9 strategies we implemented 7 additional. This study is the first step to establish AMS policy in our ICU. The next step is made assessment of the clinical impact of our AMS policy.
 Hernández-Gómez et al. Biomédica; 34 (1): 91–100, 2014
P437 Carbapenem resistant enterobacteriaceae (CRE) intraabdominal infections (IAI)
B Magazi 1, S Khan1, J Pasipanodya2
1MSD, Midrand, South Africa; 2BRI, Dallas, Texas, United States
To better inform infection control and antibiotic stewardship programs, we investigated carbapenem resistance trends and assessed the molecular characteristics of β -lactamases (ESBLs, AmpC β -lactamases and carbapenamases) among Enterobacteriaceae isolates from IAI patients treated in South African hospitals participating in the Study for monitoring Antimicrobial Resistance Trends (SMART) program 2010 and 2015.
Cochran-Armitage test was used to examine trends in susceptibility. Classification and regression trees (CART) were used to identify minimum inhibitory concentration (MIC) thresholds of various drugs as well as other factors predictive of phenotypic CRE. EUCAST version 6 MIC interpretive criteria were used to identify non-susceptible isolates. (4) Isolates recovered <48 hours after hospitalization were considered community-associated infections (CAI); while those recovered > =48 hours were considered healthcare-associated infections (HAI).
Of the 124 isolates 109 (88%) were phenotypically ESBL, 122 (98%) of these had one or more β -lactamases and ampC genes identified and 98 (79%) were fully susceptible to the carbapenems (Fig. 22). Figure 22A shows that K.pneumoniae (68/124) and E coli (42/124) were the majority isolates contributed most of the drug resistance genes identified. Carbapenem susceptibility significantly declined by an average of 35% (2-80), driven in part by increase in resistance in K pneumoniae isolates (Fig. 22B). On the contrary, susceptibility to amikacin significantly increased, while that of piperacillin/tazobactam decreased to 59%. Of the 26 isolates nonsusceptible to carbapenems; 6 (23%) were CAI and were 12 (46%) were HAI; p = 0.468 (Fig. 22C). CTXM-15 lactamase was the most frequent gene identified I 85/124 (65%) of isolates; but, was found in combination with other genes 67/81 (83%) of the time. In fact, the odds for nonsusceptibility to carbapenems rose 26-folds (3-245) when 4 genes were present compared to isolates with only one drug resistance gene was present for all isolates.
P438 Intraosseous administration of antibiotics during experimental septic shock
M Eriksson1, G Strandberg1, M Lipsey1, A Larsson2
1Surgical Sciences, Uppsala, Sweden; 2Medical Sciences, Uppsala, Sweden
Intraosseous (IO) access may be lifesaving in medical emergencies, when conventional vascular access is difficult to achieve. In life-threatening infections, early administration of antibiotics is crucial. In septic shock, the circulation is markedly compromised. We wanted to elucidate whether sufficient blood levels are reached, when antibiotics are administered IO .
A model of endotoxemic shock was used, where 8 anaesthetized, extensively monitored, pigs were given a continuous infusion of E. Coli endotoxin over 6 hour period, after which, the animals were sacrificed. The Animal Ethics Committee of Uppsala University, Sweden, approved the experiment. IO access was achieved in the tibial bone (EZ-IO®, Teleflex Medical, Morrisville, NC, USA). Cefotaxime at 75mg/kg and gentamicin at 7 mg/kg, respectively were administered IO or intravenously (IV). Central concentrations of these antibiotics were measured at 5, 15, 30, 60, 120, and 180 min.
After starting the endotoxin infusion, most of the animals showed signs of hemodynamic instability with reduced mean arterial blood pressure (MAP), cardiac index and markedly elevated mean pulmonary arterial pressure. All animals except one, needed norepinephrine to keep MAP >60 mm Hg. The plasma concentrations of both cefotaxime and gentamicin, when injected IO and IV, respectively, were nearly identical with similar slopes showing decreasing plasma concentration of each antibiotic by time. There were no significant differences between either antibiotic, regardless of injection site, based on analysis of variance. The 95% confidence intervals regarding the difference of means for each antibiotic, were well within the relevant intervals.
This study strongly suggests that IO access may be an appropriate alternative to IV administration of antibiotics, in some severe infectious conditions (e.g. septic shock), when venous access is difficult to achieve. Relevant concentrations of these antibiotics were achieved even in severely circulatory comprised animals. Thus, we deduce that IO antibiotic administration also may be considered in the prehospital setting, as early systemic administration of antibiotics may be lifesaving .
1. Strandberg et al. AAS 59: 346–53, 2015
2. Kumar et al. Crit Care Med 34:1589–96, 2006
P439 Cycling aminoglycosides in critical care: a change to antimicrobial policy
Z Rajput, F Hiscock, T Karadag, J Uwagwu, S Jain, A Molokhia
Lewisham and Greenwich NHS Trust, London, United Kingdom
Our study was carried out to audit aminoglycoside resistant patterns and assess the need to cycle aminoglycosides. The current trust antimicrobial policy at Lewisham (UHL) and Greenwich (QEH) NHS Trust advises the use of gentamicin as a first line agent against gram-negative organisms except in severe sepsis where it recommends amikacin. Antimicrobial cycling has a role in critical care due to the increasingly rapid spread of resistant bacteria, influencing healthcare costs and mortality . Of note, the rotation of gentamicin and amikacin has been found to reduce gentamicin resistance in some studies .
This was a 3-month retrospective, cross-site study from 1/8/16 – 31/10/16. Data was obtained from UHL and QEH critical care units. Resistance patterns of samples positive for gram-negative organisms were analysed using WinPath. The total number of resistant organisms were found, and within this cohort; the number of gram-negative organisms resistant to both gentamicin and amikacin. The proportion of extended spectrum beta lactamase (ESBL) and AmpC positive organisms were also analysed.
4398 samples were obtained; 2822 (64%) from UHL and 1576 (36%) from QEH. 68% of gram-negative organisms were sensitive to all antimicrobials. Within the 3 month period 1462 (33.2%) of samples displayed antibiotic resistance; of which 4% of organisms were found to be resistant to gentamicin.
This audit has demonstrated a significant number of gentamicin resistant organisms. However this does not reach the national threshold for cycling. We have noted the need to reinforce the use of amikacin as a first line aminoglycoside in all critically ill patients.
 Kollef M. Clinical Infectious Diseases. Vol 43: suppl 4: 82–88: 2006
 Kollef M. Critical Care. Vol 5: No 4: 189–195: 2001
See text for description
Other gram negatives
Total number of samples
Gentamicin sensitive-GS/ Amikacin sensitive-AS
Gentamicin resistant- GR/ AS
GR/ Amikacin resistant-AR
P440 Continuous infusion of linezolid in critically ill patients: optimizing the dosage regimen through a PK/PD analysis
H Barrasa1, A Soraluce2, E Uson1, A Rodriguez2, A Isla2, A Martin1, B Fernández1, F Fonseca1, JA Sánchez-Izquierdo3, FJ Maynar1
1Hospital Universitario Alava - Santiago, Vitoria, Spain; 2University of the Basque Country UPV/EHU, Vitoria, Spain; 3Hospital Universitario Doce de Octubre, Madrid, Spain
Linezolid (LZ) is an antibiotic with time-dependent activity. An optimal antibacterial effect is achieved when plasma drug concentrations are above the MIC (T > MIC) for the entire length of treatment. Critically ill patients receiving standard doses of LZ, particularly in those with sepsis and conserved renal function (CRF), are at risk of not attaining PK/PD targets. LZ clearance (LzCl) is usually increased in these patients, often due to augmented renal clearance (ARC). Continuous infusion (CI) could offer advantages in this context . The objective of this work was to study the benefit of CI of LZ in critically ill patients with CRF.
Study developed in two tertiary hospitals in critically ill patients in the absence of severe renal dysfunction (Creatinine clearance (CrCl) >40 ml/min). Each patient received a CI of LZ (50 mg/h) preceded by a 600 mg bolus. Blood samples were taken on days 1, 2, 3 and 4 after infusion onset. CrCl was determined on each day of the study. Treatment was considered satisfactory if steady state plasma concentration (CSS) was > =2mg/L (MIC90 of most Gram-Positive Cocci in Europe). The correlation between CrCl and LzCl was calculated. α significance level of 0.05.
22 adult patients (64% males) were included in the study (80 samples). The mean age was 55 years (SD 19), and the average weight was 81 kg (SD 19). The median and interquartile ranges (IR) were: CrCl 119 ml/min (IR 85-168), LzCl 13 L/h (IR 6-24) and Css 3.8 mg/L (IR 2.1-7.9). 55% of patients presented ARC (CrCl > =130 ml/min) and 32% of the patients had CrCl > =165 mL/min, for at least one day. CSS was > =2mg/L in 84% of the samples. The correlation (Spearman’s Rho) between CrCl and LzCl was 0.81 (p < .001). CrCl, with a cut-off point of 165 ml/min, can predict failure in treatment (CSS <2mg/L) with a sensitivity of 92% (95% CI 74-100), specificity of 86% (95%CI 77-95) and AU ROC 0.94 (95%CI 0.87-1.0).
Despite the high CrCl values of the patients, 50 mg/h LZ CI ensures a high probability of achieving the PK/PD target if CrCl < 165 ml/min. In the presence of CrCl > =165 ml/min, a higher dose should be considered.
1. Adembri, C., et al., Linezolid pharmacokinetic/pharmacodynamic profile in critically ill septic patients: intermittent versus continuous infusion. Int J Antimicrob Agents, 2008. 31(2): p. 122–9.
P441 Pharmacokinetics of tigecycline in liver impairment: quantification of liver function with maximal liver function capacity test (LiMAx test)
M Kaffarnik1, R Alraish1, O Frey2, A Roehr2, M Stockmann1, S Wicha3
1Charite Berlin Campus Virchow, Berlin, Germany; 2Pharmacy, Clinic of Heidenheim, Heidenheim, Germany; 3Uppsala University, Dept. of Pharmaceutical Biosciences, Uppsala, Sweden
Tigecycline (TGC) is a key antibiotic in the therapy of intra-abdominal infections in critically ill patients. Liver failure frequently occurs in this patient collective and may lead to altered pharmacokinetics (PK) of TGC in these patients. We aimed to (i) determine the PK of TGC in patients with and without liver impairment and to (ii) compare the value of the novel maximum liver function capacity (LiMAx) test and conventional liver function markers (ALAT, Bilirubin, INR) as covariates of TGC PK.
Patients with and without liver impairment were included in this open, prospective cohort study. All patients received an i.v. TGC loading dose of 100 mg followed by 50 mg twice daily, administered over 0.5 h. TGC plasma concentrations were determined by HPLC after >36 h of therapy at 5 time points. On the day of plasma sampling, ALT, BIL, INR and LiMAx were determined. NONMEM® 7.3 was utilised for the pharmacometric analysis.
23 patients contributed 114 timed plasma samples and supported estimation of a two-compartment PK model with linear elimination. LiMAx and BIL were low correlated (r2 = 0.11). Including both was significant for TGC clearance (CL) (p < =0.005), whereas ALT and INR were not significant. Parameter estimates (relative standard error) for a typical patient with LiMAx 187 μg/kg/h and BILI 2.1 mg/dL were: CL 9.7 L/h (7%), V1 72.4 L (15%), intercompartimental clearance Q 64.9 L/h (16%), V2 137 L (10%). Inclusion of LiMAx and BIL reduced the interindividual variability of CL from 43.3% to 30.1%. Determined CL were substantially influenced by liver function (Fig. 23; paired typical predicted CL (red) and individually determined CL (black) vs. LiMAx).
P442 Susceptibility of ceftolozane/tazobactam against isolates collected from intensive care unit patients in European hospitals (2014-2016)
D Shortridge, M Castanheira, HS Sader, JM Streit, RK Flamm
JMI Laboratories, North Liberty, Iowa, United States
Ceftolozane/tazobactam (C/T) is an antibacterial combination consisting of a novel antipseudomonal cephalosporin and a β -lactamase inhibitor. C/T was approved by the US Food and Drug Administration in 2014 and the European Medicine Agency in 2015 to treat complicated urinary tract infections, acute pyelonephritis and complicated intraabdominal infections. The Program to Assess Ceftolozane/Tazobactam Susceptibility (PACTS) monitors C/T resistance to Gram-negative (GN) isolates worldwide.
A total of 3984 GN isolates were collected in 2014-2016 from 39 European hospitals’ intensive care unit (ICU) patients and tested for susceptibility by broth microdilution method in a central laboratory. The most common source was tracheal aspirate followed by bloodstream. In addition to C/T, amikacin (AMK), cefepime (FEP), ceftazidime (CAZ), colistin (COL), levofloxacin (LVX), meropenem (MER), and piperacillin/tazobactam (TZP) were tested. Antibiotic resistant phenotypes identified using EUCAST (2016) clinical breakpoints included extended-spectrum beta-lactamase (ESBL), carbapenem-resistant Enterobacteriaceae (ENT; CRE), ceftazidime nonsusceptible (CAZ-NS), meropenem nonsusceptible (MER-NS), and multidrug resistance (MDR).
The 5 most common species isolated from ICU patients were Pseudomonas aeruginosa (PSA; 887 isolates), Escherichia coli (735), Klebsiella pneumoniae (674), Acinetobacter baumannii complex (481), and Enterobacter cloacae (181). For 2,402 ENT isolates, 82.7% were susceptible (S) to C/T (MIC of [<=]1 mg/L), AMK had 94.8% S, FEP 75.0%S, CAZ 69.6%S, COL 79.0%S, LVX 76.4%S, MER 95.1%S, and TZP 74.1%S. For 489 ENT with an ESBL (non-CRE) phenotype, and the most active drugs were COL (93.4%S) and MER (99.2%S). C/T had 64.6%S. A total of 571 ENT were MDR, 42.7% were S to C/T, 78.6%S to AMK, 20.1%S to FEP, 12.1%S to CAZ, 72.6%S to COL, 28.5%S to LVX, 79.5%S to MER and 21.9%S to TZP. A total of 118 ENT were CRE, and 56.9% were S to COL, 44.9%S to AMK, other agents were <13%S. For PSA, 85.9% were S to C/T (MIC [<=]4 mg/L), 80.0%S to AMK, 72.9%S to FEP, 67.8%S to CAZ, 99.9%S to COL, 57.8%S to LVX, 62.1%S to MER, and 64.7%S to TZP. The most active agents against the 300 MDR PSA were COL 99.7%S and C/T 59.0%S. Other agents were AMK 43.5%S, FEP 26.3%S, LVX 12.0%S, MER 14.7%S, and TZP 9.7%S.
C/T demonstrated good activity against ICU ENT isolates with 82.7%S. Only AMK and MER were more active. For PSA, C/T demonstrated potent activity (85.9%S) and was more active than all other agents tested except for COL.
P443 Clinical outcomes of ceftriaxone versus nafcillin or cefazolin for the treatment of methicillin-susceptible staphylococcal aureus bacteremia
K Falsetta, T Lam, S Reidt, J Jancik
Hennepin County Medical Center, Minneapolis, Minnesota, United States
The objective of this study was to compare clinical outcomes of ceftriaxone (CTX) vs. nafcillin (NAF) or cefazolin (CFZ) for the treatment of methicillin-susceptible staphylococcal aureus (MSSA) bacteremia. Treatment of MSSA bacteremia typically consists of oxacillin (OXA) or NAF. Retrospective data comparing CFZ to OXA for the treatment of MSSA bacteremia suggest that CFZ is an effective alternative agent, while CTX use has yielded mixed results [1, 2, 3].
This retrospective chart review included patients with positive blood cultures for MSSA who received treatment with CTX, NAF, or CFZ between the months of January 2012 and September 2016. Patients were excluded for the following reasons: receiving >3 days of non-study antimicrobial agents with activity for MSSA, age <18 years, polymicrobial blood cultures, therapy for <14 days, or if adequate source control was not achieved. Patients were assigned to one of two groups: CTX therapy or standard of care therapy (SOCT) with either NAF or CFZ. The primary outcome was rate of clinical cure at end of defined therapy for the CTX group compared to the SOCT group. Secondary outcomes evaluated were: treatment failure, time to negative blood culture, time to defervescence, and occurrence of acute kidney injury (AKI). Demographic data were collected. Clinical cure, treatment failure, and occurrence of AKI were assessed with the Fisher’s exact test. Time to negative blood culture and time to defervescence were assessed with the Mann-Whitney U test. Demographic data were assessed with descriptive statistics.
Fifty-one patients met inclusion criteria. There were no differences in clinical cure rates between CTX (81.8%) and SOCT (72.5%) (p = 0.7063). There were no differences in treatment failure between CTX (9%) and SOCT (7.5%) (p = 0.99). Median time to negative blood culture was 40 hours for CTX vs. 36.5 hours for SOCT (p = 0.45). Median time to defervescence was 13 hours for CTX and 22 hours for SOCT (p = 0.99). AKI occurred in 0 patients treated with CTX and 4 patients treated with SOCT (p = 0.5726).
In this comparison of CTX vs. SOCT for the treatment of MSSA bacteremia we found no difference in clinical cure. We also found no difference in treatment failure, time to negative blood culture, time to defervescence, and occurrence of AKI.
1. Li J et al. Antimicrob Agents Chemother. 58:5117–24, 2014.
2. Patel UC et al. Int J Clin Pharm. 36:1282–89, 2014.
3. Carr D et al. Abstract presented at IDWeek. 2015: San Diego, CA.
P444 Development of antibiotic treatment algorithms based on gram stain to restrict usage of broad-spectrum antibiotics in the treatment of ventilator-associated pneumonia: a retrospective analysis
T Kinoshita1, J Yoshimura2, K Yamakawa1, S Fujimi1
1Osaka General Medical Center, Osaka, Japan; 2Sakai City Medical Center, Osaka, Japan
Ventilator-associated pneumonia (VAP) is a common and serious problem in intensive care unit (ICU). Several studies have demonstrated that Gram stain of endotracheal aspirate may be useful for accurate diagnosis of VAP. However, the effectiveness of Gram stain on prediction of causative microorganisms has not been elucidated. The purpose of this study is to evaluate whether Gram stain of endotracheal aspirates can be used as a guide of initial antibiotic therapy for VAP.
Data on consecutive episodes of microbiologically confirmed VAP were collected from February 2013 to February 2016 in our ICU. We constructed 2 hypothetical empirical antibiotic treatment algorithms for VAP. The first algorithm was the guideline based algorithm (GLBA) that based on the recommendation of American Thoracic Society-Infectious Diseases Society of America guidelines. The second one was the Gram stain based algorithm (GSBA) that limited spectrum of the initial antibiotic therapy according to the results of bed-side Gram stain. Subsequently, the GLBA and the GSBA were retrospectively reviewed in the same VAP episodes. The initial coverage rates and the recommendation of broad-spectrum antibiotics was compared between the two algorithms.
During the study period, 219 suspected VAP episodes were observed and 131 episodes were assessed for analysis. Appropriate antibiotic coverage rates were equivalent in the two algorithms (GLBA: 94.7% vs GSBA: 92.4%, p = 0.221). The number of episodes that anti-methicillin resistant Staphylococcus aureus agents were recommended as an initial treatment was larger in GLBA than GSBA (70.2% vs 31.3%, p < 0.001). Furthermore, the number of episodes that antipseudomonal agents were recommended as an initial treatment was also larger in GLBA than GSBA (70.2% vs 51.9%, p < 0.001).
The GSBA may restrict the administration of broad-spectrum antibiotics without increasing risk of treatment failure.
P445 Efficacy of murepavadin co-administered with standard-of-care in a phase 2 study in patients with ventilator-associated pneumonia due to Pseudomonas aeruginosa infection
A Armaganidis1, A Torres2, S Zakynthinos3, C Mandragos4, E Giamarellos-Bourboulis5, P Ramirez6, M De la Torre-Prados7, A Rodriguez8, G Dale9, A Wach9, L Beni9, L Hooftman9, C Zwingelstein 9
1National and Kapodestrian University of Athens, Athens, Greece; 2Hospital Clinic, Barcelona, Spain; 3Evangelismos Hospital Medical School of Athens, Athens, Greece; 4Korgialenio-Benakio E.E.S, Athens, Greece; 5University General Hospital “ATTIKON”, Athens, Greece; 6Hospital Universitario Politècnic la Fe, Valencia, Spain; 7Hospital Universitario Virgen de la Victoria, Malaga, Spain; 8Hospital Universitario de Tarragona Joan XXIII, Tarragona, Spain; 9Polyphor Ltd, Allschwil, Switzerland