Dr. Widayat Djoko Santoso, Sp.PD.KPTI1967-1972 SD Tulungagung II1973-1975 SMP II Tulungagung1976-1979SMA/SMPP Tulungagung1979-1987FK Unair1987-1988Dokter on shore1988-1990Ka Puskesmas Pagerwojo1990-1994Ka Puskesmas Rejotangan1994-2000Spesialis FK UI2000-skrgStaf Divisi penyakit Tropic & Infeksi departemen Ilmu penyakit dalam FK UI - RSCM2005 Konsultan penyakit tropic & infeksi FK UI2007 Sedang menempuh studi S3

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Dengue Hemorrhagic Fever, Clinical Management in Adult Patients.

Dr. Widayat Djoko S. SpPD-KPTI

Division of Tropical & Infectious Diseases.Internal Medicine Department . Faculty of Medicine. University of Indonesia. Cipto Mangunkusumo, Central Referral General Hospital.

Kapan dirawat RS?Puskesmas perawatan?Rawat jalan? Kapan boleh pulang rawat?

Masukan ibu Dirjen PPBBMasukan Peserta PertemuanDualisme Protokol Penatalaksanaan !

**Manifestations of dengue infectionDengue virus infectionAsymptomaticSymptomaticUndifferentiated feverDengue fever syndromeWithout haemorrhageWith unusual haemorrhageDengue haemorrhagic feverNo shockDengue shock syndromeDengue feverDengue haemorrhagic feverIIIIIIIVNo leakagePlasma leakage

Kriteria Diagnosis DBD (WHO 1997) Demam/ riwayat demam akut jangka waktu 2-7 hari. Trombositopenia (< 100.000/mm3) Manifestasi perdarahan diantaranya sbb: Uji tourniquet positif, petekie, ekimosis, purpura. Perdarahan mukosa, GIT, bekas iv. Line. Hematemesis, melena. Terdapat plasma leakage dg tanda sbb: Ht meningkat > 20%. Ht turun > 20% pasca pemberian cairan. Efusi pleura, asites , hiponatremia, hipoalbuminemia.

Permasalahan klinis.Bila rawat jalan, sulit diprediksi akan manifes sbg Dengue Klasik atau DBD/SSD. BOR sarana kesehatan sangat tinggi.Tiadanya data hematokrit normal ( tiap populasi yg sesuai umur & jenis kelamin) atau data Ht tiap individu saat sehat. Penentuan kenaikan Ht tak dpt dihitung.Pasien dipulangkan sebelum fase normal. data Ht saat pulang tak dpt dipakai untuk menghitung hemokonsentrasi.

Virus isolationMolecular techniquesDengue antigen capture ELISA -4 -2 0 2 4 6 8 10 12Day of Illness ShockHemorrhagePlaque Reduction Neutralization TestHemagglutination InhibitionIgM and IgG ELISARapid testsAnti-dengue AbCourse of Dengue Infection/DxMosquitobiteviremia

**PROTOKOL 1. PENANGANAN TERSANGKA ( PROBABLE ) DBD DEWASA TANPA SYOK

**Suspek DBDPerdarahan Spontan dan Masif (-)Syok (-)- Hb,Ht (n)- Tromb. 20% Tromb.

**PROTOKOL 3. PENATALAKSANAAN DBD DENGAN PENINGKATAN HT > 20 % 5 % defisit cairanTerapi awal i.v. Kristaloid 6-7 ml/kg/jamTatalaksana sesuaiProtokol syok danProtokol syok daN perdarahan Terapi cairandihentikan24-48 jam PERBURUKANHt, nadi meningkat,Tensi turunproduksi urin menurunKurangi infus kristaloid5 ml/kg/jamTANDA VITAL DANHEMATOKRITMEMBURUKPERBAIKANPERBAIKANTIDAKMEMBAIKPERBAIKANHt & nadi turun,Tensi perbaikanproduksi urin meningkat,PERBAIKANInfus kristaloid15 ml/kg/jamKONDISI MEMBURUKTanda syokEvaluasi 3-4 jam PERBAIKANKurangi infus kristaloid3 ml/kg/jamInfus kristaloid10 ml/kg/jam

**

PERBAIKAN Kristaloid: 7 ml/kg/jam dlm 1 jamKristaloidGuyur 20-30 ml/kgBB; 20-30 menitKembali ke awalPERBAIKANPERBAIKANKristaloid: 5 ml/kg/jam dlm 1 jamKristaloid: 3 ml/kg/jam dalam 1 jamPerhitungkan nutrisi stlh 12 jam (D 5% bila tak ada kontraindikasi)24 48 jam pasca syok teratasi, tanda vital / Ht stabil, diuresis cukupStop infuskoloid 10-20 ml/kgBBtetes cepat 10-15 menitHt Ht SYOKPERBAIKAN Koloid (hinggamaksimal 30 ml/kgBBPERBAIKAN Kristaloid dipantau10 15 menitTETAP SYOKKombinasiKoloid kristaloidPerbaikanbertahap vasopresorditurunkan10-20 cc/kgBB 20-30 menit; O2 2 - 4 L/menAGD Elektrolit * (Bila ada fasilitas).Hb, Ht, trombosit, leukosit, urea, Kreatinin,

Jika SDM nya tersedia & terlatih Untuk anak tidak direkomendasikanPasangCVP***Koreksi gangguan asam basa, elektrolit, hipoglikemia, anemia, KID, infeksi sekunderHipovolemikNormovolemikKoloid ** bila sebelumnya belum dipakai atau kristaloid / gelatin bila koloid sebelumnya telah mencapai dosis maksimal 10 ml/kg dalam 10 menit dapat diulang sampai 30 ml/kg sasaran CVP 15 18 smH2O 8 12 mmHg SYOKPROTOKOL 5: TATALAKSANA SYOK PADA DBD SYOKTanda vital / HtKoreksi asam basa, elektrolit, hipoglikemia, anemia, KID, infeksi sekunder- Inotropik- Vasopresor- Afterload SYOKPerbaikanTransfusi darah segar10 ml/kgBB dapat diulang sesuai kebutuhan BURUK

Kriteria Pemulangan pasien DBDTidak demam selama 24 jam tanpa antipiretikNafsu makan membaikKlinis tampak perbaikanHematokrit stabilTiga hari setelah renjatan teratasiJumlah trombosit > 50.000 dg tren meningkat.Tidak dijumpai distres pernafasan

Dengue feverSearch date November 2004Marissa M AlejandriaIntravenous fluids, crystalloids or colloids?

Kesimpulan: tidak ada perbedaan bermakna diantara keduanya.

Management.No specific treatment.Cut multiple cascade syndrome to prevent snowball phenomenon.Supportive treatment.Keep normal intravascular fluids volume.Stabilize Homodynamic performance. Prevent stagnation of the micro vascular circulation. Adequacy of oxygenation.Clinical manifestation depend on a time during the illness.

**Dengue Hemorrhagic Fever: What is a crucial time ?

widayat - KPPIK FKUI

**Available Our Study. ND: Non Dengue. Ig M (-); Ig G (-).DP: Primary Dengue. Ig M (+); Ig G (-).DS: Secondary Dengue Ig M (+); Ig G (+).Total Sample:ND: Male = 23. Female= 15.DP: Male = 13. Female= 18.DS: Male = 41. Female= 22.Criteria DiagnosticMeet WHO 1997.Ultrasound examination on 5-7th day of illness.Rapid serology(Pan Bio) on 7-8th day of illness.

**Available Our Study. ND: Non Dengue. Ig M (-); Ig G (-).DP: Primary Dengue. Ig M (+); Ig G (-).DS: Secondary Dengue Ig M (+); Ig G (+).Total Sample:ND: Male = 23. Female= 15.DP: Male = 13. Female= 18.DS: Male = 41. Female= 22.Criteria DiagnosticMeet WHO 1997.Ultrasound examination on 5-7th day of illness.Rapid serology(Pan Bio) on 7-8th day of illness.

**Available Our Study. Total Sample:ND: Male = 23. Female= 15.DP: Male = 13. Female= 18.DS: Male = 41. Female= 22.Plasma volume loss equation:% PV= 100 X 100(Ht 1- Ht 2) 100-Ht 1 Ht 2Ht 1: Hematocrite pre dehydration.Ht 2: Hematocrite post dehydration.

References: more than 30 article.Davy KP, Seals DR. J Appl Physiol.1994;76(5):2059-62.Weddesland R, Brown E,HopperJ. J Clin Invest.1959;38:1065-77.Van Beaumont W, Greenleaf JE. J Appl Physiol.1972;33(1):55-61.Dill DB, Costill DL.J Appl Physiol.1974;37(2):247-8.

Plasma leakage in Dengue Hemorrhagic FeverPathogenesis, clinical consequences & management.

Definition.Leakage of intravascular fluids into the extravascular space1,2 due to widening of the endothelial gaps3,4. Hypovolemia, hemoconcentration, weakness, edema, and visceral congestion are resulting consequences. 1. Vaughn DW.et al. J Infect Dis.1997;176:322-30. 2. Duane J. Gubler. Clin Microbiol Rev. 1998 July; 11(3): 480496. 3. McDonald DM, Thurston G, Baluk P. Microcirculation 1999;6(1): 7-22.4. Dejana E. J Clin Invest 1997;100(11):S7-S10.

Physiologic Process Mechanism.Plasma leakage is a normal physiologic process of fluid homeostasis mechanism.5,6

Depend on gravitation, physical activity, plasma osmolarity, oncotic plasma pressure.

Note: Systemic capillary leak syndrome as a consequences of Systemic Inflammatory Syndrome is a pathogenic mechanism due to inflammatory cytokine. 5. Lundvall J, J Appl Physiol.1994;77(5):2155-62.6. Hagan RD, J Appl Physiol.1978;45(3):414-18.

Pathologic condition. Uncompensated failure of fluid homeostatic mechanism.7Over extravasations due to fluid overfilled.Failure of the pump (cardiac), excretion (renal), pulmonary blood flow stagnation (COPD), mesenteric blood flow stagnation (intra abdominal mass), lymph node obstruction, hepatic failure.Systemic vascular leakage syndrome.SIRS, sepsis, DSS. 7.Hinghofer-szalkay HG,. J Appl Physiol.1995;78(4):1369-73

Leakage of intravascular fluids into the extravascular space*,** due to widening of the endothelial gaps#,##. Hypovolemia, hemoconcentration, weakness, edema, and visceral congestion are resulting as consequences. Systemic capillary leak syndrome as a consequences of Systemic Inflammatory Syndrome is a pathogenic mechanism due to inflammatory cytokine.*. Vaughn DW.et al. J Infect Dis.1997;176:322-30. **. Duane J. Gubler. Clin Microbiol Rev. 1998 July; 11(3): 480496. #. McDonald DM, Thurston G, Baluk P. Microcirculation 1999;6(1): 7-22.##. Dejana E. J Clin Invest 1997;100(11):S7-S10.Pathologic Process Mechanism.

Pathologic Process Mechanism.Endothelial gaps as sites for plasma leakage in inflammation that caused by loosen Inter endothelial cell adherens junction.* Opening endothelial gaps process is a complex mechanism that depend on biochemical substance (proinflamatory cytokine), biomechanical factors (shear stress) and individual host responses.+,#*. McDonald DM, Thurston G, Baluk P. Microcirculation 1999;6(1): 7-22.+. Dejana E. Endothelial adherens junctions. J Clin Invest 1997;100(11):S7-S10.#.Ballermann BJ, Dardik A, Eng E, Liu A. Shear stress and the endothelium. Kidney International 1998;54(67):S100-S108.

Severity of capillary leak syndrome : Depend on gaps size & local or broad area.Matrix composition of perivascular compartments.Hydrostatic and oncotic pressure differences between intra-extra vascular. Zimmerman GA, McIntyre TM, Prescott SM. J Clin Invest 1997;100(11):S3-5.Pathologic Process Mechanism.

Activated platelets Degranulation of Microgranules.Expresion of Molecule Adhesion.

Clinical Consequences.Platelet activation& agregation

Clinical Consequences.Hipovolemia Vasokonstriksi vaskulerSnowball phenomenon.

Management of microcirculatory in Septic Shock.Widayat Djoko S.Suhendro.

Division of Tropical & Infectious Diseases.Internal Medicine Department . Faculty of Medicine. University of Indonesia. Cipto Mangunkusumo Hospital.

Sepsis is a disease of the microcirculation Spronk P, Zandstra D, Ince C (2004) Critical Care 8:462-468

Why is microcirculation important?.It is where oxygen exchange takes place.Every parameter in the microcirculation is different than in the systemic circulation.It plays a centrol role in the immune system.It is the target organ of shock It is the first organ to dysfunction in the development of MOFS.During sepsis and shock it the first to go and last to recover.Rescue of the microcirculation = the resuscitation end-point.Ince C (2005) Critical Care 9:S13-S19

Co-morbidityGenesInitial HitCirculatory Shock + InflammationResuscitation based oncorrection of systemic hemodynamics+ inflammationMicrocirculatory DysfunctionTimeTherapyRBC

Deformability,AggregationO2 transportCoagulation

Natural AnticoagulantsMicrovascular ThrombosisLeukocytes

Adhesion, Cytokines, ROSEndothelial Dysfunction

Barrier, CommunicationCoagulation, RegulationDysfunction Autoregulation

Microcirculatory shunting supply-demand mismatchHypoxiaCellular Distress

MitochondriaHibernationApoptosis Organ Failure

TimeTherapyThe Microcirculation is the Motor of Sepsis

Hemodynamic support in septic shock. Hypovolemic, cardiogenic, and obstructive shock occurs as a result of decrease in cardiac output leading to anaerobic tissue metabolism.

Septic shock results from distributive alterations in tissue perfusion caused by abnormal control of microvasculature with abnormal distribution of a normal or increased cardiac output.

Hence end-points have been difficult to define.

Vincent JL.Intensive Care Medicine (2001) 27:S80-S92

The Endothelial-Circulating Cells-Plasma Fluid Relationship.Inflammatory activationCoagulatory /RBC dysfunctionEndothelial barrier dysfunctionCapillary fall out Weak microcirculatory units are shuntedHypoxia, apoptosis, organ dysfunctionNot detected by systemic variablesInce C (2005) Critical Care 9:S13-S19

Background.Resuscitated patient fail to improvement.Normalized or supranormal O2 deliveryHi lactate, disturbed acid-base hi gastric CO2 hyperdynamic.Where is the oxygen debt? Microcirculatory shuntingHow to monitor it? Direct observation with OPS/SDF imaging How to treat it? Microcirculatory recruitment procedures.Exploring the microcirculation.

Autoregulatory control2 mEndothelialcellGlycocalyx0.2 mRed blood cellBarrier function0xygen handling

The complexities of the Trias Virchows.Capillary plugging and collapse Endothelial dysfunctionLoss of auto regulationWeak microcirculatory units are shuntedRegional hypoxic areasMitochondrial dysfunction

Microcirculatory hypoxia not corrected by conventional resuscitation strategy

Shunting model of sepsisO2lactateCO2vaImplication : that active recruitment of the microcirculationis an important component of resuscitation.Ince C & Sinaasappel M (1999) Crit Care Med 27:1369-1377

Scoring sub-lingual microcirculatory abnormalites in septic patients.Boerma EC et al. (2005) Quantifying bedside-derived imaging g of microcirculatory abnormalities in septic patients: a prospective validation study. Critical Care 9:R601-R606Trzeciak (2006) Early Microcirculatory Perfusion Derangements in Patients WithSevere Sepsis and Septic Shock[Ann Emerg Med.De Backer D et al. (2002) Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med. 166:98-104.

Measurement of functional microcirculatory geometry and velocity distributions using automated image analysis.

Medical & Biological Engineering & Computing (in press)Dobbe JGG, Streekstra GJ, Atasever B, van Zijderveld R, Ince C (2008)

Velocity analysis small vesselsVessel Length (m)0100Time (sec)04132entryexitAverage velocity 195 53 m/s

Microcirculation Recruitment Manoeuvres Ince C (2005) Critical Care 9:S13-S19

Correct pathological flow heterogeneity, microcirculatory shunting and restore autoregulatory dysfunction by control of inflammation, vascular function and coagulation. Avontuur (1997) Cardiovas Res 35:368-376. Siegmund M (2005) Inten Care Med 31:985-992. Open the microcirculation and keep it open by support of the pump, fluids, vasodilators and restricted use of vasopressor agents. : Boerma (2005) Acta Anaesthesiol Scand. 49(9):1387-90. Spronk (2001) The Lancet 360:1395-1396 Siegemund (2006) Intensive Care Med

Conclusions Distributive shock has a bad prognosis with difficult to define hemodynamics end-points.2) It causes a distributive defect at the capillary level of the microcirculation causing functional shunting of weak microcirculatory units.3) It is the reason why distributive shock cannot be adeqautely monitored by systemic hemodynamic parameters.4) OPS/SDF en tissue capnography provide an integrative evaluation of the functional state of the microcirculation.5) Microcirculatory Recruitment Maneuvres are affective in correcting distributive shock

Kesimpulan Potong kaskade secepatnya.

Filsafat menimba ilmu.Bak botol kosong tak bertutupYang slalu tengadah keatasMengharap kucuran airDan takkan pernah penuh

Matur suwun

******Poschl Kaplan 2001 *********