CPG 2010- Management of Dengue Infection in Adults (Revised 2nd Ed 2010) (1)

8/6/2019 CPG 2010- Management of Dengue Infection in Adults (Revised 2nd Ed 2010) (1)

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MINISTRY OF HEALTH MALAYSIA ACADEMY OF MEDICINE MALAYSIA

CLINICAL PRACTICE GUIDELINESMOH/P/PAK/174.08 (GU)


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Review of the Guidelines

These guidelines were issued in 2010 and will be reviewed in

2014 or sooner if new evidence becomes available.

CPG Secretariat

Health Technology Assessment Section

Medical Development Division

Ministry of Health Malaysia

4th Floor, Block E1, Parcel E

62590 Putrajaya.

Electronic version available on the following websites :

http://www.moh.gov.my

http://www.acadmed.org.my

These are Clinical Practice Guidelines on Management of Dengue

Infection in Adults (Revised 2nd Edition) 2010. The CPG supersede the

previous CPG on Management of Dengue Infection in Adults (2nd Edition) 2008.

These guidelines are meant to be guides for clinical practice,

based on the best available evidence at the time of develoment.

Adherence to these guidelines may not necessary guarantee

the best outcome in every case. Every healthcare provider is

responsible for the management of his/her unique patient

based on the clinical picture presented by the patient and

the management options available locally.


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GUIDELINES DEVELOPMENT AND OBJECTIVE

GUIDELINES DEVELOPMENT

The development group or these guidelines consisted o a amily medicine

specialist, an emergency medicine specialist, a general physician, inectious

disease physicians, intensivists, haematologists, public health physicians,

a virologist and a nursing sister rom the Ministry o Health and Ministry o

Higher Education, Malaysia. During the process o development o these

guidelines, there was active involvement o a review committee.

The previous edition o CPG (2003) was used as the basis or the

development o these present guidelines.

These guidelines provide:

a. A detailed description o the clinical course o dengue illness which

reects the dynamism and systemic nature o dengue that have crucial

bearing on the patients management.

b. A detailed description o the basic pathophysiological changes o

severe dengue (i.e. plasma leakage and hypovolemia/shock) and

provide guidance on the recognition o these changes and appropriate

action o management.

c. A brie discussion on WHO Classifcation (1997) and its limitations.

d. Some useul guides on the dierential diagnoses that can be conused

with dengue or vice versa; they were described according to the stage

o disease.

e. A more ocused guide on the disease monitoring in accordance with

the dynamic changes as the disease progresses.

. Emphasis on the importance o monitoring the plasma leakage (clinical

signs o plasma leakage and haematocrit (HCT) and haemodynamic

status o the patients.

g. Clearer algorithm on uid management in severe dengue.

h. Emphasis on the importance o recognising or suspecting signifcant

occult bleed with some useul guides.

i. A more systematic approach on the recognition o signs o recovery.

Literature search was carried out at the ollowing electronic databases:

International Health Technology Assessment Website, PUBMED, Cochrane

Database o Systemic Reviews (CDSR), Journal ull text via OVID search

engine, Comprehensive; Database o Abstracts o Reviews o Eectiveness,


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Cochrane Controlled Trials Registered, CINAHL via EBSCO search

engine. In addition, the reerence lists o all relevant articles retrieved were

searched to identiy urther studies. Reerence was also made to other

guidelines WHO Dengue Haemorrhagic Fever: Diagnosis, Treatment,

Prevention and Control, WHO Geneva, 1997; Guidelines, Guidelines or

DHF Case Management, Bangkok, Thailand 2002; Guidelines on Clinical

Management O Dengue Fever / Dengue Haemorrhagic Fever 2005 SriLanka; WHO Regional Publication SEARO, 1999; Guidelines or Treatment

o Dengue Fever/Dengue Hemorrhagic Fever in Small Hospitals, WHO

Regional Ofce or SE Asia, New Delhi, 1999. There were very ew studies

carried out on dengue patients in the adult population. Many o the studies

included in these guidelines are based upon the management o dengue

in children. The fndings o these studies were then extrapolated on to the

adult population, taking into consideration our local practices.

The clinical questions were divided into major subgroups and memberso the development group were assigned individual topics within these

subgroups. The group members met a total o 15 times throughout the

development o the guidelines. All literature retrieved were appraised by

at least two members and presented in the orm o evidence tables and

discussed during group meetings. All statements and recommendations

ormulated were agreed by both the development group and review

committee. Where the evidence was insufcient the recommendations were

derived by consensus o the development group and review committee.

The articles were graded using the modifed version o the criteria used

by the Catalonia Agency or Health Technology Assessment and Research

(CAHTAR) Spain, while the grading o recommendation in this guideline

was modifed rom the Scottish Intercollegiate Guidelines Network (SIGN).

The drat guidelines was posted on both the Ministry o Health Malaysia

and Academy o Medicine, Malaysia websites or comment and eedback.

These guidelines had also been presented to the Technical AdvisoryCommittee or Clinical Practice Guidelines, and the Health Technology

Assessment and Clinical Practice Guidelines Council, Ministry o Health

Malaysia or review and approval.


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OBJECTIVES

GENERAL OBJECTIVES

To provide evidence-based guidance in the management o dengue

inection in adult patients

SPECIFIC OBJECTIVES

To improve recognition and diagnosis o dengue cases and provide

appropriate care to the patients

To identiy severe dengue and carry out more ocused close monitoring

and prompt appropriate management

To provide guidance on appropriate and timely uid management andthe use o blood and blood products

To improve on early and accurate notifcation o dengue cases or

prompt public health intervention

CLINICAL QUESTIONS

Please reer to Appendix 6

TARGET POPULATION

Adult patients with dengue ever, dengue haemorrhagic ever or dengue

shock syndrome and other orms o severe dengue.

TARGET GROUP/USER

These guidelines are applicable to primary care doctors, public health

personnel, nurses, assistant medical ofcers, physicians and critical care

providers involved in treating adult patients with dengue ever, dengue

haemorrhagic ever or dengue shock syndromeand other orms o severedengue.

HEALTHCARE SETTINGS

Both outpatient and inpatient settings


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CLINICAL INDICATORS FOR QUALITy MANAGEMENT

PRIMARy INDICATORS

i. Case atality rate (DF & DHF)

Numerator: No o DF & DHF/DSS death

Denominator: No o DF & DHF cases (clinically diagnosed)

National target (9th Malaysian Plan):< 0.2%

ii. DHF atality rate

Numerator: No o DHF/ DSS death

Denominator: No o DHF/ DSS cases (clinically diagnosed)

National target (9th Malaysian Plan):


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GUIDELINES DEVELOPMENT GROUP

CHAIRPERSON

Dr. Mahiran Mustaa

Senior Consultant Inectious Disease Physician

Hospital Raja Perempuan Zainab II

Kota Bharu Kelantan

MEMBERS(alphabetical order)

Dr. Abdul Hamid Jaaar

Assistant Director

Communicable Disease Control Division

Ministry o Health

Dr. Norita Ahmad

Consultant Inectious Disease Physician

Hospital Raja Perempuan Zainab II

Kelantan

Dr. Ainul Nadziha Mohd. Hanafah

Assistant DirectorHealth Technology Assessment Section

Medical Development Division, MOH

Dr. Salmah Idris

Consultant PathologistHospital Sungai Buloh

Selangor

Dr. Chow Ting Soo


Hospital Pulau Pinang

Pulau Pinang

Dr. Sheamini Sivasampu

Principal Assistant Director


Medical Development Division MOH

Dr. Faisal Salikin

Emergency Medicine Specialist

Hospital Kuala Lumpur

Kuala Lumpur

Ms Sin Lian The

Nursing Sister


Medical Development Division MOH

Dato Dr. Faraizah Abdul Karim

Deputy Director

National Blood Centre Kuala Lumpur

Dato Dr. K. Sree Raman

Senior Consultant Physician

Hospital Tuanku Jaaar

Negeri Sembilan

Dr. Ho Bee Kiau

Family Medicine Specialist

Bukit Kuda Health ClinicSelangor

Dr. Suresh Kumar


Hospital Sungai BulohSelangor

Dr Mohamad Ikhsan Selamat

Principal Assistant Director

Communicable Disease Control Division

Ministry o Health

Dr. Tan Cheng Cheng

Senior Consultant Intensivist and

Anaesthesiologist

Hospital Sultanah Aminah Johor

Dr. Jameela Sathar

Senior Consultant Haematologist

Hospital Ampang Selangor

Dr. Tan Lian Huat

Lecturer and Inectious Disease Physician

University Malaya Medical Centre

Selangor

Dr. Lim Chew Har

Consultant Intensivist & Anaesthesiologist


Pulau Pinang


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REVIEW COMMITTEE(alphabetical order)

The drat guidelines was reviewed by a panel o independent expert reerees

rom both public and private sectors, who were asked to comment primarily

on the comprehensiveness and accuracy o interpretation o the evidence

supporting the recommendations in the guideline.

Dr. Christopher Lee

Senior Consultant Inectious Disease Physician

Hospital Sungai Buloh

Selangor

Proessor Luc Lum Chai See

Proessor o Paediatrics

University Malaya Medical Centre

Selangor

Datin Paduka Dr. Santha Kumari


Hospital Tengku Ampuan Rahimah

Selangor

Dr. Radhakrishnan Sothiratnam

Consultant Physician

Columbia Asia Medical CentreNegeri Sembilan

Dr. Rud yeoh Seok Ching

Consultant Haematologist

S. C. Yeoh Haemotology Consultancy Sdn Bhd

Kuala Lumpur

Datin Dr. Rugaah Bakri

Deputy DirectorHealth Technology Assessment Section

Medical Development Division

Ministry o Health

Dr. Tai Li Ling

Senior Consultant Intensivist & Anaesthesiologist


Kuala Lumpur


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EXTERNAL REVIEWERS(alphabetical order)

The ollowing external reviewers provided eedback on the drat

Dr. Alan Teh

Consultant Physician & Haematologist

Subang Jaya Medical Centre

Selangor

Dr. Maimunah Mahmud

Family Medicine Specialist

Klinik Kesihatan Jinjang

Kuala Lumpur

Dr. Chua Kaw Beng

Consultant Virologist

National Public Health Laboratory

Ministry o Health

Sungai Buloh, Selangor

Dato Dr. Ravindran Jegasoth

Head o Department and Senior

Consultant O&G


Kuala Lumpur

Dr. Jearam Menon

Senior Consultant Gastroenterologist

& Head o Department

Hospital Queen Elizabeth

Sabah

Dr. Rashidi Ahmad

Emergency Physician/Lecturer

Hospital Universiti Sains Malaysia

Kelantan

Dato Dr. ST Kew


International Medical University

Kuala Lumpur

Assoc. Pro. Dr. Shaiul Bahari Ismail

Lecturer and Family Medicine Specialist

Hospital Universiti Sains Malaysia

Kelantan

Dr. G. R. Letchuman Ramanathan


Hospital Taiping

Perak

Dr. Tan It

Consultant Anaesthetist

Sunway Medical Centre

Selangor

Dato Dr. Lim yu Hoe



Pulau Pinang

Dr. S Visalach Purushothaman

Senior Consultant Haematologist

Hospital Ampang

Selangor

Dr. Mahathar Abdul Wahab

Emergency Medicine Specialist


Kuala Lumpur

Dr. yoong Kar yaw

Consultant Physician

Hospital Sultan Ismail

Johor


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TABLE OF CONTENTS

GUIDELINES DEVELOPMENT AND OBJECTIVE i

GUIDELINES DEVELOPMENT COMMITTEE v

REVIEW COMMITTEE vi

EXTERNAL REVIEWERS vii

TABLE OF CONTENT viii

1. EPIDEMIOLOGY 1

2. VIROLOGY 3

3. CLINICAL MANIFESTATIONS AND PATHOPHYSIOLOGY 3

3.1 SPECTRUM OF DENGUE INFECTION 3

3.2 CLINICAL COURSE OF DENGUE INFECTIONi.Febrile Phase

ii.Critical Phase

iii.Recovery Phase

44

4

5

3.3 PATHOPHYSIOLOGY OF PLASMA LEAKAGE IN DENGUE

HAEMORRHAGIC FEVER (DHF) / DENGUE SHOCK SYNDROME (DSS)

6

3.4 TOURNIQUET TEST 8

3.5 WHO DENGUE CLASSIFICATION

3.5.1 Limitations o WHO classifcation3.5.2 Suggested WHO Classifcation 2009

8

89

3.6 OTHER IMPORTANT MANIFESTATIONS 9

3.7 DIAGNOSTIC CHALLENGES 10

4. DISEASE NOTIFICATION 11

5. LABORATORY INVESTIGATIONS 12

5.1 DISEASE MONITORING LABORATORY TESTS 12

5.2 DIAGNOSTIC TESTS

5.2.1 Dengue Serology Tests

5.2.2 Virus Isolation

5.2.3 Polymerase Chain Reaction (PCR)

5.2.4 Non-structural Protein-1 (NS1 Antigen)

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13

15

15

15

6. INVESTIGATION OF POST MORTEM CASE 16

7. MANAGEMENT OF DENGUE INFECTION 16

7.1 OUTPATIENT MANAGEMENT 16

7.2 PATIENT TRIAGING AT EMERGENCY AND

OUTPATIENT DEPARTMENTS

18

7.3 CRITERIA FOR HOSPITAL REFERRAL / ADMISSION

7.3.1 Reerral rom Primary Care Providers to Hospital

7.3.2 Reerral rom Hospitals Without Specialist to Hospital with

Specialists

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19

19


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7.4 DISEASE MONITORING

7.4.1 Principles o Disease Monitoring

7.4.2 Outpatient Disease Monitoring

7.4.3 Inpatient Disease Monitoring

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20

20

20

7.5 FLUID MANAGEMENT

7.5.1 Dengue with Warning Signs7.5.2 Non-shock Patients (DHF Grade I & II)

7.5.3 Dengue Shock Syndrome (DSS) (DHF Grade III &IV)

23

2324

ALGORITHM A - FLUID MANAGEMENT IN COMPENSATED SHOCK

ALGORITHM B - FLUID MANAGEMENT IN DECOMPENSATED SHOCK

27

28

7.6 MANAGEMENT OF BLEEDING/HAEMOSTASIS

7.6.1 Haemostatic Abnormalities in Dengue Inection

7.6.2 How to Recognize Signifcant Bleeding?

7.6.3 Management o Bleeding in Dengue7.6.4 Management o Upper Gastrointestinal Bleeding (UGIT)

7.6.5 The Role o Prophylactic Transusions in Dengue

7.6.6 The Role o Adjunctive Therapy in Dengue

29

29

29

2930

30

30

7.7 INTENSIVE CARE MANAGEMENT

7.7.1 Indications or Respiratory Support (Non-invasive and

Invasive Ventilation)

7.7.2 Indications or Haemodynamic Support

7.7.3 Guide on Saety and Risk o Invasive Procedures

31

31

31

32

8. DISCHARGE CRITERIA 33

9. PREVENTION OF DENGUE TRANSMISSION IN HOSPITALS 33

10. VACCINATION 34

11. DENGUE IN PREGNANCY 34

REFERENCES 36

APPENDIX 1 -WORLD HEALTH ORGANIZATION CLASSIFICATION

OF DF AND DHF (1997)

46

APPENDIX 2 -Methods o Sample Collection 48

APPENDIX 3 - Home Care Advice Leaet 49

APPENDIX 4 -Disease Monitoring Card 50

APPENDIX 5 - Dengue Monitoring Chart 51

APPENDIX 6 - Clinical Questions 52

APPENDIX 7 - Search Strategy 54

LIST OF ABBREVIATIONS 55

ACKNOWLEDGEMENT 56

DISCLOSURE STATEMENT 56

SOURCES OF FUNDING 56

LEVELS OF EVIDENCE & GRADES OF RECOMMENDATION


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1. EPIDEMIOLOGyDengue is one o the most important arthropod-borne viral diseases in

terms o human morbidity and mortality. Dengue has become an important

public health problem. It aects tropical and subtropical regions around the

world, predominantly in urban and semi urban areas.

The number o reported dengue ever (DF) and dengue haemorrhagic

ever (DHF) cases in Malaysia shows an increasing trend (Figure 1). The

incidence rate also shows an upward trend rom 44.3 cases/100,000

population in 1999 to 181 cases/100,000 population in 2007 (Figure 2).

This exceeds the national target or the incidence rate o DF and DHF

which is less than 50 cases/100,000 population. Dengue ever accounts

or almost 95% o all reported cases. The serologically confrmed cases

are approximately 40-50% o these cases at the time o notifcation. This

relatively low percentage o seropositivity is due to lack o convalescent

samples (second blood specimen) being sent or confrmation.

The incidence rate is higher in the age group o 15 years and above (Figure

2). The highest incidence rate is among the working and school-going age

groups. An increase o dengue deaths in the adult population has been

observed since 2002 (Figure 3). The case atality rates or both DF and DHF

however remain well below 0.3% since 2002 (Figure 4).

Most o the dengue cases reported were rom urban areas (70 80%)

where there is a high density o its population and rapid development

activities actors which avour dengue transmission.

6,543

14,255

19,429

27,381

10,146

7,103

16,368

32,76731,545

33,895

39,65438,556

46,542

79.6

43.040.9

50.2

46.5

52.5 52.9

47.348.9

39.642.5

47.3

29.5

0

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

90.0

SerologyPositve(%)

Total DF DHF Serology Positive (%)

6,543

14,255

19,429

27,381

10,146

7,103

16,368

32,76731,545

33,895

39,65438,556

49,173

79.7

42.540.9

50.2

46.2

52.4 53.0

47.349.0

39.6

42.7

47.348.7

0

10

20

30

40

50

60

70

80

90

100

0

10,000

20,000

30,000

40,000

50,000

60,000

SerologyConfirmed(%)

Noofcases

Year

Total (Clinical) DF DHF Serologically Confirm ed (%)

Figure 1 : Number o Dengue Cases, Malasia 1995-2007


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0

10

20

30

40

50

60

70

80

90

1999 2000 2001 2002 2003 2004 2005 2006 2007Year

NoO

fDeath

0 - 14 Years (IR) > 15 Years (IR)

0.36

0.63

0.31 0.300.23

0.30 0.280.23

0.20

0.00

0.20

0.40

0.60

0.80

1.00

1.20

1.40

1999 2000 2001 2002 2003 2004 2005 2006 2007

Incide

nce(per100,0

00)

Year

Population (CFR) 0 - 14 Years (CFR) > 15 Years (CFR)

44.330.2

68.2

133.6 125.9 132.5

151.9144.7

181

0

50

100

150

200

250

1999 2000 2001 2002 2003 2004 2005 2006 2007Year

Incidence

(per

100,

000)

Population 0 - 14 Years > 15 Years

Figure 3 : Dengue Deaths b Age Group in Malasia, 1999-2007

Figure 2 : Dengue Incidence Rate b Age Group in Malasia, 1999-2007

Figure 4 : Dengue Case Fatalit Rate (CFR) b Age in Malasia, 1999-2007


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2. VIROLOGyDengue inection is caused by dengue virus which is a mosquito-borne

avivirus. It is transmitted by Aedes aegypti and Aedes albopictus. There

are our distinct serotypes, DEN-1, 2, 3 and 4. Each episode o inection

induces a lie-long protective immunity to the homologous serotype but

coners only partial and transient protection against subsequent inection

by the other three serotypes. Secondary inection is a major risk actoror DHF due to antibody-dependent enhancement. Other important

contributing actors or DHF are viral virulence, host genetic background,

T-cell activation, viral load and auto-antibodies.

All our serotypes can be isolated at any one time but the predominant

circulating dengue virus will show a sinusoidal pattern (Figure 5). For

example, DEN-3 was the predominant serotype in the early 90s with a peak

in 1993, and then subsequently declined. It then re-emerged, reaching the

peak in 2001. Other serotypes had been observed to be co-circulating at

the same time

3. CLINICAL MANIFESTATIONS AND PATHOPHySIOLOGy

3.1 SPECTRUM OF DENGUE INFECTION

The incubation period or dengue inection is 4-7 days (range 3-14).2 It

may be asymptomatic or may result in a spectrum o illness ranging rom

undierentiated mild ebrile illness to severe disease, with or withoutplasma leakage and organ impairment. Symptomatic dengue inection is a

systemic and dynamic disease with clinical, haematological and serological

profles changing rom day to day. These changes accelerate by the hour

or even minutes during the critical phase, particularly in those with plasma

leakage (reer to section 3.3).

0

10

20

30

40

50

60

70

80

90

100

%o

fSerotype

Den 1 (%) Den 2 (%) Den 3 (%) Den 4 (%)

Figure 5 : Percentage o Dengue Serotpe in Malasia, 1991-2007


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Understanding the systemic and dynamic nature o dengue disease as well

as its pathophysiological changes during each phase o the disease will

produce a rational approach in the management o dengue

3.2 CLINICAL COURSE OF DENGUE INFECTION

Dengue inection is a dynamic disease. Its clinical course changes as the

disease progresses. Ater the incubation period, the illness begins abruptly

and will be ollowed by 3 phases: ebrile, critical and recovery phase (reer

Figure 6). 3, 4

i. Febrile Phase

Typically, patients develop high grade ever suddenly. This acute ebrile

phase usually lasts 2-7 days and oten accompanied by acial ushing,

skin erythema, generalised body ache, myalgia, arthralgia and headache.3,4

Some patients may have sore throat, injected pharynx and conjunctivalinjection. Anorexia, nausea and vomiting are common. These clinical

eatures are indistinguishable between DF and DHF.5

Mild haemorrhagic maniestations like positive tourniquet test or petechiae

and mucosal membrane bleeding may be seen in DF and DHF.5,6 Per

vaginal bleeding is common among young adult emales. Massive vaginal

bleeding and gastrointestinal bleeding may occur during this phase but

are not common.7, 6 The fndings o an enlarged and tender liver are more

suggestive o DHF.5

The earliest abnormality in the ull blood count is a progressive decrease

in total white cell count. This should alert the physician to a high index

o suspicion o dengue especially when there is positive history o

neighborhood dengue. This disease should be notifed as early as possible

to prevent disease rom assuming epidemic proportion.

ii. Critical Phase

The critical phase occurs towards the late ebrile phase (oten ater 3rd day

o ever) or around deervescence (usually between 3rd to 5th day o illness

but may go up to 7th day) when a rapid drop in temperature may coincide

with an increase in capillary permeability in some patients. In other viral

inections, the patients condition improves as the temperature subsides,

but the contrary happens in DHF. At this point the patient will either become

better i no or minimal plasma leak occurs, or worse i a critical volume o

plasma is lost.3, 4,8, 9

The critical phase lasts about 24-48 hours. (reer Figure 6) Varying

circulatory disturbances (reer to Table 1) can develop. In less severe cases,

these changes are minimal and transient. Many o these patients recover

spontaneously, or ater a short period o uid or electrolyte therapy. In

more severe orms o plasma leakage, the patients may sweat, become

restless, have cool extremities and prolonged capillary refll time. The

pulse rate increases, diastolic blood pressure increases and the pulse

pressure narrows. Abdominal pain, persistent vomiting, restlessness,


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altered conscious level, clinical uid accumulation, mucosal bleed or

tender enlarged liver are the clinical warning signs o severe dengue or high

possibility o rapid progression to shock.9, 10, 11 The patient can progress

rapidly to proound shock and death i prompt uid resuscitation is not

instituted.

It is important to note that thrombocytopaenia and haemoconcentration(evidenced by a raised haemotocrit (HCT) rom baseline or a drop in HCT

ater rehydration) are usually detectable beore the subsidence o ever

and the onset o shock. Reer to 3.5.1 or urther details. The HCT level

correlates well with plasma volume loss and disease severity. However, the

levels o HCT may be equivocal when there is rank haemorrhage, early and

excessive uid replacement or untimely HCT determinations.

Leucopaenia with relative lymphocytosis, clotting abnormalities, elevation

o transminases [typically the level o aspartate aminotransaminase(AST) is about 2-3 times the level o alanine aminotransaminase (ALT)],

hypoproteinaemia and hypoalbuminaemia are usually observed.3, 4, 5

iii. Recover Phase

Ater 24-48 hours o deervescence, plasma leakage stops and is ollowed

by reabsorption o extravascular uid. Patients general well being improves,

appetite returns, gastrointestinal symptoms abate, haemodynamic status

stabilises and diuresis ensues. Some patients may have a classical rasho isles o white in the sea o red.3 Some may experience generalised

pruritus. Bradycardia and electrocardiographic changes are not uncommon

during this stage. It is important to note that during this phase, HCT level

stabilises or drops urther due to haemodilution ollowing reabsorption o

extravascular uid. The recovery o platelet count is typically preceded by

recovery o white cell count (WCC).

Figure 6 : CLINICAL COURSE OF DHF12

Note : Onset o deervescence usually occurs between day 3 to day 5 o illness

40

Viraemia

Course ofdengue illness FEBRILE CRITICAL RECOVERY

Shock / Bleeding Reabsorption / Fluid overloadDehydration

Days of illness

Temperature

Potential

clinical issues

Laboratory

changes

Serology

and virology

Platelet

Hematocrit

IgM/IgG

Organ Impairment

1 2 3 4 5 6 7 8 9 1 0

REVISEDJULY 2010


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Clinical deterioration oten occurs during the critical phase

(plasma leakage) and it is thereore crucial to recognise the

onset o this phase.

The onset o critical phase is marked by plasma leakage and

usually occurs around the onset o deervescence.

Evidence o plasma leakage includes raised HCT (early marker),

haemodynamic instability, uid accumulation in extravascular

space (rather late marker) or hypoproteinemia.

Abdominal pain, persistent vomiting, restlessness, altered

conscious level, clinical uid accumulation, tender enlarged

liver or mucosal bleed are the clinical warning signs o severe

dengue or high possibility o rapid progression to shock.

3.3 PATHOPHySIOLOGy OF PLASMA LEAKAGE IN DENGUEHAEMORRHAGIC FEVER (DHF)/DENGUE SHOCK SyNDROME (DSS)

The primary pathophysiological abnormality seen in DHF and DSS is an

acute increase in vascular permeability that leads to leakage o plasma

into the extravascular compartment, resulting in haemoconcentration and

hypovolaemia or shock.13,3,4 Hypovolaemia leads to reex tachycardia and

generalised vasoconstriction due to increased sympathetic output.14,15

Clinical maniestations o vasoconstriction in various systems are as

ollows :

a. Skin - coolness, pallor and delayed capillary refll time

b. Cardiovascular system - raised diastolic blood pressure and a narrowing

o pulse pressure

c. Renal system - reducing urine output

d. Gastrointestinal system - vomiting and abdominal pain

e. Central nervous system lethargy, restlessness, apprehension, reduced

level o consciousness

. Respiratory system tachypnoea(respiratory rate >20/min)

In patients whose consciousness is not obtunded, intense thirst is another

prominent symptom. At the same time, the inadequate perusion o the

tissue leads to increased anaerobic glycolysis and lactic acidosis. I the

hypovolaemia is not corrected promptly, the patient will progress to a

reractory shock state. By then, the tissue perusion would not respond to

vasopressor drugs, even i the blood pressure and intravascular volume

were to be restored and cardiac output would remain depressed. The

resultant lactic acidosis urther depresses the myocardium and worsensthe hypotension.15 The common late complications o prolonged shock

are massive bleeding, disseminated intravascular coagulopathy (DIC) andmulti-organ ailure which are oten atal.

The ollowing table is the summary o the continuum o various

pathophysiological changes in a patient who progresses rom normal

circulatory state to hypovolaemic shock.

REVISEDJULY 2010


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Table 1 : A continuum o pathophsiological changes rom normal circulation to

compensated and decompensated/ hpotensive shock(Adapted rom15)

Normal Circulation Compensated shockDecompensated /

Hpotensive shock

Clear consciousnessClear consciousness shock can be

missed i you do not touch the patient

Change o mental state restless,

combative or lethargy

Brisk capillary refll time (2 sec)Mottled skin, very prolonged

capillary reil l time

Warm and pink extremities Cool extremities Cold, clammy extremities

Good volume peripheral pulses Weak & thready peripheral pulses Feeble or absent peripheral pulses

Normal heart rate or age TachycardiaSevere tachycard ia wi th

bradycardia in late shock

Normal blood pressure or age

Normal systolic pressure with

raised diastolic pressure

Postural hypotension

Hypotension/unrecordable BP

Normal pulse pressure or age Narrowing pulse pressureNarrowed pulse pressure

(


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3.4 TOURNIQUET TEST

In DHF grade 1, a positive tourniquet test serves as the only indicator ohaemorrhagic tendency. The sensitivity o the test varies widely rom as lowas 0% to 57%, depending on the phase o illness the test was done andhow oten the test was repeated, i negative. In addition 5-21% o patientswith dengue like illness had positive tourniquet test but subsequently have

negative dengue serology.22, Level 1

A recent study demonstrated that there was 95.3% positive preditivevalue i ever, positive tourniquet test, leucopenia/ thrombocytopaenia/haemoconcentration were used as screening criteria.23, Level 8

The tourniquet test may be useul as an additional tool when the diagnosis

is in doubt, especially when the platelet count is still relatively normal.

How to perorm tourniquet testInate the blood pressure cu on the upper arm to a point midway

between the systolic and diastolic pressures or 5 minutes.

A positive test is when 20 or more petechiae per 2.5 cm (1 inch)

square are observed.

Recommendation

The tourniquet test may be helpul in the earl ebrile phase (less

than three days) in dierentiating dengue rom other ebrile illnesses.(Grade C)

3.5 WHO DENGUE CLASSIFICATION

Based on current WHO dengue classifcation scheme (reer Appendix 1), thekey dierentiating eature between DF and DHF is the presence o plasmaleakage in DHF. However, in the early ebrile phase o dengue inection,the symptoms can overlap and one cannot dierentiate DF and DHF.

DHF is urther classifed as mild (grades I and II) or severe (grades III andIV), the presence o shock being the main dierence. Grades III and IV areclassifed as Dengue Shock Syndrome (reer Appendix 1).

(Note : The existing WHO dengue classifcation is being reviewed and revised)

3.5.1 Limitations o WHO classifcation22, Level 1

It has been observed that the existing WHO classifcation scheme hasseveral limitations as the disease has spread to new regions and inected

older age groups. For example:1. Dengue with shock without ulflling all the 4 criteria or DHF

There have been many case reports o patients with severe dengue with shockwho do not ulfl all the 4 criteria or DHF. These patients would have beenclassifed as dengue ever i the WHO criteria are to be strictly applied.

2. Severe organ impairmentPatients with severe organ impairment such as liver, respiratory,cardiac and brain dysunction are not captured as having severe

disease based on the existing classifcation.


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3. Plasma leakage in DHF

The requirement o 20% increase in HCT as one o the evidence oplasma leakage is difcult to ulfll due to several issues:

a. Baseline HCT is not available in most patients and thereore, theinterpretation o plasma leak can only be made retrospectively

b. Early uid administration may aect the level o HCTc. Bleeding will aect the HCT level

4. The existing classifcation scheme is oten not useul or diseasemanagement because the correct disease classifcation can only bemade towards the end o the illness.

Patients can present with severe dengue without ulfllingALL the4 criteria (reer Appendix 1) or DHF/DSS.

3.5.2 Suggested WHO Classifcation 2009The classifcation into levels o severity has a high potential or being opractical use in the clinicians decision as to where and how intensivelythe patient should be observed and treated (i.e. triage, which is particularlyuseul in outbreaks).

Figure 7: Suggested Dengue Classifcation and Level o Severit

Source: World Health Organization. Dengue Guidelines or Diagnosis, Treatment,Prevention and Control - New Edition 2009. WHO: Geneva; 2009

3.6 OTHER IMPORTANT MANIFESTATIONS

Severe bleeding or organ impairment might occur without plasma leakage.The Following maniestations are important in dengue inection but areoten under- recognised or misdiagnosed:

Figure 1.4 Suggested dengue case classification and levels of serverity

DENGUE + WARNING SIGNS SEVERE DENGUE

Probable denguelive in/ travel to dengue endemic area.

Fever and 2 of the following criteria:

l Nausea, vomitingl Rash

l Aches and pains

l Torniquet test positive

l Leukopenia

l Any warning sign

Laboratory-confirmed dengue(important when no sign of plasma leakage)

Warning signs*

l Abdominal pain or tenderness

l Persistent vomiting

l Clinical fluid accumulation

l Mucosal bleed

l Lethargy, restlessness

l Liver enlargment > 2cm

l Laboratory: increase in HCT concurrentwith rapid decrease in platelet count

* (requiring strict observation and medical intervention)

CRITERIA FOR SEVERE DENGUE

Severe plasma leakage leading to :

l Shock (DSS)

l Fluid accumulation with respiratory distress

Severe bleedingas evaluated by clinician

Severe organ involvement

Liver : AST or ALT > = 1000

CNS : Impaired consciousness

Heart and other organs

1. Severe plasma leakage

2. Severe haemorrhage

3. Severe organ impairment

with warning signs

without

CRITERIA FOR DENGUE + WARNING SIGNS

REVISEDJULY 2010


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1. Acute abdomen :

Acute abdominal pain is a common symptom in dengue inection. It can

be due to hepatitis, acalculous cholecystitis and shock, and occasionally

misdiagnosed as acute appendicitis.24, Level 8; 25, Level 8 The history o

onset o ever beore the abdominal pain, and laboratory fndings o

leucopenia, thrombocytopenia, or prolonged APTT with normal PT

help to dierentiate acute abdominal pain due to dengue inection romother surgical causes.24, Level 8 Furthermore, in patients with shock, the

abdominal pain is relieved by intravenous uid therapy.

2. Hepatitis and liver ailure :

Hepatitis is common in patients with DF/DHF and may be mild or

severe regardless o the degree o plasma leakage. In some cases,

liver ailure may occur.22,Level 1 The patients with liver ailure have a high

propensity to bleed, especially gastrointestinal bleeding. 26, Level 8; 11, Level 8

3. Neurological maniestation :

Patients with dengue inection may have neurological maniestations,

(


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FEBRILE PHASE

Table 2 : Dierential diagnoses or dengue illness during ebrile phase

Clinical sndrome Dierential diagnoses

Flu-like sndrome

Inuenza

Measles

Chikungunya

AdenovirusInectious mononucleosis

Acute HIV seroconversion illness

Rash

Rubella

Measles

Scarlet ever

Meningococcal inection

Chikungunya

Drug

DiarrheaRotavirus

Food poisoning

Neurological maniestationMeningoencephalitis

Febrile seizures

CRITICAL PHASETable 3:Dierential diagnoses or dengue illness during critical phase

Clinical sndrome Dierential diagnoses

Acute abdomen

Acute appendicitis

Acute cholecystitisPerorated viscus

Viral hepatitis

Diabetic ketoacidosis

Shock Septic shock

Respirator distress

(Kussmauls breathing)

Diabetic ketoacidosis

Renal ailure

Lactic acidosis

Leucopaenia &

thromboctopenia bleeding

Acute leukaemiaImmune thrombocytopaenia purpura

Thrombotic Thrombocytopenic purpura

Malaria / Leptospirosis / Typhoid / Typhus

Bacterial sepsis

SLE

Acute HIV seroconversion illness

4. DISEASE NOTIFICATION

All suspected dengue cases must be notifed by telephone to the nearesthealth ofce within 24 hours o diagnosis, ollowed by written notifcationwithin a week using the standard notifcation ormat.29 Any delay in notifcationwill increase the risk o dengue transmission in the locality o the residence.In 2007, 98.4% o dengue cases were notifed by public and private hospitalswith only 1.6% rom the government and private clinics. The average day oillness at the time o notifcation was about 4-5 days ater the onset o illnesseven though patients might have presented themselves to the healthcare

acilities at day 1-3 day o ever.


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Notifcation should be done as soon as a clinical diagnosis o dengue is

suspected; serological confrmation is not necessary. Notifed cases will be

ollowed up by the health authorities or the verifcation o case defnition

and preventive measures. It is also important to note that re-notifcation

has to be done i the diagnosis has been changed rom DF to DHF or DF

to other diagnosis.

Failure to notiy is liable to be compounded under the Prevention and

Control o Inectious Diseases Act, 1988 (Act 342).30

5. LABORATORy INVESTIGATIONS

5.1 DISEASE MONITORING LABORATORy TESTS

Full Blood Count (FBC)

1. White cell count (WCC) :

In the early ebrile phase WCC is usually normal but will decreaserapidly as the disease progresses.5, Level 8 This trend o leucopenia

should raise the suspicion o possible dengue inection.

2. Haematocrit (HCT) :

A rising HCT is a marker o plasma leakage in dengue inection and

helps to dierentiate between DF and DHF but it can be masked in

patients with concurrent signifcant bleeding and in those who receive

early uid replacement.22, Level 1 Setting the patients baseline HCT in the

early ebrile phase o disease will be very useul in the recognition o

a rising HCT level.

3. Thrombocytopaenia :

Thrombocytopaenia is commonly seen in dengue inection.22,Level 1 In

the early ebrile phase, platelet count is usually within normal range

but it will decrease rapidly as the disease progresses to the late ebrile

phase or at deervescence and it may continue to remain low or the

frst ew days o recovery.

There is a signifcant negative correlation between disease severity

and platelet count 3, Level 9;31Level 8 but it is not predictive o bleeding.32,

Level 8; 33, Level 1; 34, Level 6;35, Level 8; 36, Level 8

Liver Function Test

Elevated liver enzymes is common and is characterised by greater elevation o

the AST as compared to the ALT.37,Level 8 The requency and degree o elevation

o the liver enzymes are higher with DHF compared to DF.

38, Level 8;

37, Level 8


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Leucopaenia ollowed by progressive thrombocytopaenia is

suggestive o dengue inection.

A rising HCT accompanying progressive thrombocytopaenia is

suggestive o DHF.

There is no local data available on the normal range o HCT in adults.

In the absence o a baseline HCT level, a HCT value o >40% in

emale adults and >46% in male adults should raise the suspicion

o plasma leakage.

Recommendation

The baseline HCT and WCC should be established as early aspossible in all patients with suspected dengue. (Grade A)

Serial FBC and HCT must be monitored as the disease progresses.

(Grade A)

5.2 DIAGNOSTIC TESTS

Defnitive diagnosis o dengue inection can only be confrmed in the

laboratory. However, the interpretation o laboratory diagnostic results

should be done in the clinical context. Laboratory confrmatory tests includeantibody detection (serology), virus isolation, detection o virus genetic

materials (polymerase chain reaction -PCR) and detection o dengue virus

protein (NS1 antigen).

5.2.1 DENGUE SEROLOGy TESTS

Haemagglutination Inhibition Test

The haemagglutination Inhibition (HI) test has been the gold standard or

serological diagnosis. However, because it is labour intensive and requires

paired samples or interpretation, this test is now being used mainly orresearch purposes to dierentiate between primary and secondary dengue

inections.

Dengue IgM test

The IgM capture enzyme-linked immunosorbent assay (ELISA) is the most

widely used serological test. This antibody titre is signifcantly higher in

primary inections, compared to secondary inections. Once the IgM is

detectable, it rises quickly and peaks at about 2 weeks ater the onset o

symptoms, and it wanes to undetectable levels by 60 days. However insome patients, it may persist or more than 90 days. A positive result thus

has to be intepreted and correlated cautiously with the clinical picture. I

the dengue IgM test is the only available diagnostic test in the hospital,

then establishing a negative IgM early in the illness, and demonstrating a

positive serology later will be essential to exclude alse negative results.


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In one study, IgM was detected in only 55% o patients with primary dengue

inections between day 4-7 onset o ever, and it became positive in 100%

o the patients ater day 7. However, in secondary dengue inections, IgM

was detected in only 78% o patients ater day 7.39, Level 7. In another study,

28% o secondary dengue inections were undiagnosed when IgM was the

only test perormed.4, Level 9; 40,Level 8; 41, Level 8

Indirect IgG ELISA test

In primary and secondary dengue inection, dengue IgG was detected in

100% o patients ater day 7 o onset o ever. Thereore dengue IgG is

recommended i dengue IgM is still negative ater day 7 with the negative

IgG in the initial test sample.39, level 7; 40, level 8; , level 8

Please reer to Appendix 2 or methods o sample collection

Dengue Rapid tests

Simple rapid tests such as the strip assays (immunochromatography test)

are available or qualitative detection o dengue IgM and IgG (e.g. Pan Bio

Dengue IgM ELISA and Dengue IgM Dot Enzyme Immunoassay).

The yield o rapid tests was shown to be higher when samples were

collected later in the convalescent phase o inection, with good specifcity

and could be used when ELISA test were not available 43, Level 1 But the

result had to be interpreted in the clinical context because o alse positive

and negative results.44,Level 8;45, Level 8; 41, Level 8; 46, Level 8 It isrecommended that

the dengue IgM Capture ELISA test be done ater a rapid test, to confrm

the status.44,Level 8

Note : False positive dengue serolog

Serological tests or dengue have been shown to cross-react with: other avivirus Japanese Encephalitis.47, Level 9; 41, Level 8

non-avivirus malaria, leptospirosis, toxoplasmosis, syphilis48,Level ; 45, Level 8

connective tissue diseases rheumatoid arthritis44, Level 8

Recommendation

In order to establish serological confrmation o dengue illness aseroconversion o dengue IgM needs to be demonstrated. Thereorea dengue IgM should be taken as soon as the disease is suspected.(Grade C)

Dengue IgM is usually positive ater day 5-7 o illness. Thereore anegative IgM taken beore day 5-7 o illness does not exclude dengueinection. (Grade B)

I dengue IgM is negative beore day 7, a repeat sample must be takenin recovery phase. (Grade B)

I dengue IgM is still negative ater day 7 with negative IgG tested at lessthen 7 days, dengue IgG is recommended or diagnostic confrmation.(Grade C)


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5.2.2 VIRUS ISOLATION

Virus isolation is the most defnitive test or dengue inection. It can only be

perormed in the lab equipped with tissue culture and other virus isolation

acilities. It is useul only at the early phase o the illness. Generally, blood

should be collected beore day 5 o illness; i.e. beore the ormation o

neutralizing antibodies.

During the ebrile illness, dengue virus can be isolated rom serum, plasma

and leucocytes. It can also be isolated rom post mortem specimens. The

monoclonal antibody immunouorescence test is the method o choice or

identifcation o dengue virus. It may take up to two weeks to complete the

test and it is expensive.

Note: Virus isolation has a poor yield i compared with molecular tests. It is most probably due

to the viability o the virus and the quality o the samples.49,Level 8

5.2.3 POLyMERASE CHAIN REACTION (PCR)

Molecular tests such as the reverse transcriptase ploymerase chain

reaction (RT- PCR) are useul or the diagnosis o dengue inection in the

early phase (< 5 days o illness). It was shown to have a sensitivity o 100%

in the frst 5 days o disease, but reduced to about 70% by day 6, ollowing

the disappearance o the viraemia.50, Level 8;42, Level 8; 51, Level 8

An additional advantage o RT- PCR is the ability to determine dengueserotypes 52, Level 7; 42, Level 8; 53, Level 8; 49, Level 8; 54, Level 8

Limitations o RT- PCR are:

a) This test is only available in a ew centres with acilities and trained

personnel (e.g. IMR, HKL, National Public Health Laboratory and University Malaya

Medical Centre).

b) The test is expensive

c) The specimen requires special storage temperatures and short

transportation, time between collection and extraction (reer Appendix 1)

In view o these limitations, the use o RT- PCR should only be considered

or in-patients who present with diagnostic challenges in the early phase

o illness.

5.2.4 NON-STRUCTURAL PROTEIN-1 (NS1 Antigen)

NS1 antigen is a highly conserved glycoprotein that seems to be essential

or virus viability. Secretion o the NS1 protein is a hallmark o avivirus

inecting mammalian cells and can be ound in dengue inection as well

as in yellow ever and West Nile virus inection. This antigen is present inhigh concentrations in the sera o dengue inected patients during the early

phase o the disease.55, Level 8; 56,Level 8

The detection rate is much better in acute sera o primary inection (75%-

97.3%) when compared to the acute sera o secondary inection (60% -

70%).57, Level 8;58, Level 8;59, Level 8;60, Level 8 The sensitivity o NS1 antigen detection

drops rom day 4-5 o illness onwards and usually becomes undetectable

in the convalescence phase.61,Level 8;60, Level 8; 58,Level 8;59,Level 8


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Table 4 : A Stepwise Approach On Outpatient Management o Dengue Inection

It is important to evaluate every patient in a stepwise manner as in the ollowing :

Step 1: Overall assessment1. History

Date of onset of fever/ illness

Oral intake Assess for alarm signs refer to Table 5

Diarrhoea

Bleeding

Change in mental state/seizure/dizziness

Urine output (frequency, volume and time of last voiding)

Other important relevant histories:

- Family or neighbourhood history o dengue

- Jungle trekking and swimming in waterall (consider leptospirosis, typhus, malaria)

- Recent travel

- Recent unprotected sexual or drug use behaviour (consider acute HIV seroconversion illness)

- Co-morbidities (consider sepsis particularly in patients with diabetes mellitus)

2. Physical examination

i. Assess mental state and Glasgow Coma Scale (GCS) score

ii. Assess hydration status

iii. Assess haemodynamic status

- Skin colour

- Cold/ warm extremities

- Capillary flling time (normal


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1 8

Table 5 : Warning signs 8, level 8, 9, level 8

Abdominal pain or tenderness

Persistent vomiting

Clinical uid accumulation (pleural effusion, ascites)

Mucosal bleed

Restlessness or lethargy

Tender enlarged liver

Laboratory : Increase in HCT concurrent with rapid decrease in platelet

Table 6 : Clinical and Laborator Criteria or Patients Who Can be Treated at Home

1. Able to tolerate orally well, good urine output and no history o bleeding

2. Absence o clinical alarm signals (reer Table 5)

3. Physical examination:

Haemodynamically stable-pink, warm extremities

-normal capillary flling time (normal 20mmHg)

-no disproportionate tachycardia

No tachypnoea or acidotic breathing

No hepatomegaly or abdominal tenderness

No bleeding maniestation

No sign o pleural eusion ascites No alterations in mental state and ull GCS score

4. Investigation:

Stable serial HCT

In the absence o a baseline HCT level, a HCT value o >40% in emale adults

and >46% in male adults should raise the suspicion o plasma leakage.

Thereore admission may be required

Adapted rom65, Level 9; 66, Level 9; 67,Level 9

7.2 PATIENT TRIAGING AT EMERGENCy & TRAUMA / OUTPATIENT DEPARTMENTThe purpose o triaging patients is to determine whether they require urgent

attention. This is to avoid critically ill patients being missed upon arrival.

68, Level 9; 65 Level 9; 69,Level 9;70, Level 9

Triage Checklist:

1. History o ever

2. Abdominal pain

3. Vomiting

4. Dizziness/ ainting

5. Bleeding

Vital parameters to be taken :

Mental state,blood pressure, pulse, temperature, cold or warm peripheries

REVISEDJULY 2010


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7.3 CRITERIA FOR HOSPITAL REFERRAL / ADMISSION

7.3.1 Reerral rom primar care providers to hospital

The decision or reerral and admission must not be based on a single clinical

parameter but should depend on the Total Assessment o the patient.

Reerral rom primar care providers to hospital1. Symptoms :

Alarm signals (reer to Table 5)

Bleeding maniestations

Inability to tolerate oral uids

Reduced urine output

Seizure

2. Signs :

Dehydration

Shock (reer to Table 1)

Bleeding

Any organ ailure

3. Special Situations :

Patients with co-morbidity e.g.Diabetes, Hypertension, Ischaemic

Heart Disease, Coagulopathies, Morbid Obesity, Renal Failure,Chronic Liver disease, COPD,

Elderly (more than 65 years old)

Pregnancy

Social actors that limit ollow-up e.g. living ar rom health

acility, no transport, patient living alone, etc

4. Laboratory Criteria: Rising HCT accompanied by reducing platelet count

7.3.2 Reerral From hospitals without specialist to hospitals with specialists

Early consultation with the nearest physician should be initiated orALL

DHF or DF with organ dysunction/ bleeding.

Prerequisites or transer

1. All eorts must be taken to optimise the patients condition beore

and during transer.

2. The Emergency Departmentand/orMedical Department o the receiving

hospital must be inormed prior to transer.

3. Adequate and essential inormation must be sent together with the

patients that includes uid chart, monitoring chart and investigation

results.


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7.4 DISEASE MONITORING

7.4.1 Principles o Disease Monitoring

1. Dengue is a systemic and dynamic disease. Thereore disease

monitoring is governed by dierent phases o the disease.

2.The critical phase (plasma leakage) may last or 24-48 hours. Monitoring

needs to be intensifed and requent adjustments in the uid regimemay be required.

3. Recognition o onset o reabsorption phase is also important

because intravenous uid regime needs to be progressively reduced/

discontinued at this stage.

7.4.2 Outpatient Disease Monitoring

Every patient suspected o dengue attending the outpatient/ emergency

and trauma department should be assessed in stepwise manner asrecommended in Table 4.

Daily or more requent ollow up is necessary especially rom day 3 o

illness, until the patient becomes aebrile or at least 24- 48 hours without

antipyretics. A disease monitoring record has been developed and it is

recommended to be used or outpatient care (reer to Appendix 4.).

7.4.3 Inpatient Disease Monitoring

Immediately ater admission every patient with suspected dengue shouldbe reviewed thoroughly similar to the stepwise approach in outpatient (reer

to Table 4).The plan o management and monitoring should be based on

the phase o the disease and the haemodynamic status o the patient.

Table 8 summarises the parameters and requency o monitoring according

to the dierent phases o the illness.


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Table 7: Issues o Monitoring According to Dierent Phases O Dengue Illness

Phases o illness Issues :

Febrile

- Dierentiation o dengue illness rom other ebrile

illnesses.

- Not possible to dierentiate DF rom DHF.

Critical

- Plasma leakage occurs as patient progresses to

late ebrile phase or as temperature begins to

deervescence (T < 38.0 C).

- Clinical deterioration occurs during this phase due to

plasma leakage.

- Plasma leakage results in haemoconcentration and

hypovolemia/ shock.

- Excessive plasma leakage due, in part, to intravenous

uid therapy may cause respiratory distress.

- Bleeding can be precipitated by prolonged shock and

shock can be perpetuated by bleeding.

- May mimic acute abdomen o other causes.

- May be conused with septic shock or other orms

o shock.

Reabsorption

- Cessation o plasma leakage.

- Reabsorption o uid rom extravascular compartment.

- Haemodilution occurs ollowing uid reabsorption.

- Hypervolaemia and pulmonary oedema i intravenous

uid therapy is continued.


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Table 8 : Parameters and Frequenc o Monitoring According to Dierent

Phases o Dengue Illness

Parameters or monitoringFrequenc o monitoring

Febrile phase Critical phase Recover phase

Clinical Parameters

General well being

Appetite/ oral intake

Warning signs

Smptoms o bleeding

Neurological/ mental state

Daily or more

requently towards

late ebrile phase

At least twice a

day and more

requently as

indicated

Daily or more

requently as

indicated

Haemodnamic status

Pink/cyanosis

Extremities(cold/warm)

Capillaryrelltime

Pulsevolume PR

BP

Pulsepressure

Respirator status

RR

SpO2

4-6 hourly

depending on

clinical status

2-4 hourly

depending on

clinical status

In shock

Every 15-30

minutes till

stable then 1-2

hourly

4-6 hourly

Signs o bleeding, abdominal

tenderness, ascites and

pleural eusion

Daily or more

requently towards

late ebrile phase

At least twice a

day and more

requently asindicated

Daily or more

requently as

indicated

Urine output 4 hourly

2-4 hourly

In shock

Hourly

4-6 hourly

Parameters or monitoringFrequenc o monitoring

Febrile phase Critical phase Recover phase

Clinical Parameters

FBC + HCT

Daily or more

requently i

indicated

4-12 hourlydepending on

clinical status

In shock

Repeated

beore and

ater each

attempt o uid

resuscitation

and as

indicated

Daily

BUSE/ Creatinine

LFT

RBS

Coagulation profle

HCO3/ TCO

2/ Lactate

As indicated

At least daily or

more requently

as indicated

In shock

Crucial to

monitor acid-

base balance/

ABG closely

As indicated

Adapted rom 2, Level 9; 65, Level 9


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7.5 FLUID MANAGEMENT

7.5.1 Dengue with Warning Signs (reer to Table 5)

Recognising and monitoring or warning signs are crucial in identiyingpatients who may deteriorate into severe dengue.

All patients with warning signs should be considered for monitoring

in hospitals. Common pitfalls in uid therapy:

* Treating patient with unnecessary uid bolus based on raised

* HCT as the sole parameter without considering other clinicalparameters

* Excessive and prolonged fxed uid regime in stable patients

* Inrequent monitoring and adjustment o inusion rate

* Continuation o intravenous uid during the recovery phase

Cases o dengue with warning signs will probably recover with earlyintravenous rehydration. Some cases will deteriorate to severe dengue. Ithe patient has dengue with warning signs, the action plan should be as

in Table 9a.Table 9a: Action Plan or Patient who has Dengue with Warning Signs

Obtain a baseline HCT beore uid therapy.

Give crystalloids solution (such as 0.9% saline).

Start with 5-7 ml/kg/hour or 1-2 hours, then reduce to 3-5 ml/kg/hr or 2-4 hrs

and then reduce to 2-3 ml/kg/hr or less according to the clinica response. I the clinical parameters are worsening and HCT is rising, increase the rate o

inusion.

Reassess the clinical status, repeat the HCT and review uid inusion rates

accordingly

7.5.2 Non-Shock Patients (DHF Grade I & II)There are no studies that have looked at uid therapy in non shock denguepatients. Increased oral uid intake may be sufcient in some patients who are

haemodynamically stable and not vomiting. However IV uid (0.9% saline isrecommended) is indicated in patients with increasing HCT (indicating on-goingplasma leakage) despite increased oral intake. IV uid therapy should also beconsidered in patients who are vomiting and not tolerating orally.71, level 9; 65, level 9

The normal maintenance requirement or IV uid therapy in such patientscould be calculated based on the ormula in Table 9b. Frequent adjustmento maintenance uid regime is oten needed during the critical phase.Oten 1.2-1.5 times the normal maintenance will be required during thecritical phase. I the uid inusion rate exceeds more than the maintenance

requirement, the inusion rate should be reviewed within 4 to 6 hours.

A rising HCT AND/ OR haemodynamic instability indicates on-goingplasma leakage and will require an increase in the IV uid inusion rate. Ipatients deteriorate and progress to shock, uid resuscitation is indicated(reer to the section on 7.5.3).71, level 9; 65, level 9

Reduce or consider discontinuation o IV uid therapy when patients beginto show signs o recovery (usually ater 24-48 hours o deervescence, orthe HCT drops in a stable patient).

REVISEDJULY 2010


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2 4

Table 9b : Calculations for normal maintenance of intravenous uid infusion

* Normal maintenance uid per hour can be calculated based on

the ollowing ormula (Equivalent to Hallida-Segar ormula) :

4 mL/kg/h or frst 10kg body weight

+ 2 mL/kg/h or next 10kg body weight

+ 1 mL/kg/h or subsequent kg body weight* For overweight/obese patients calculate normal maintenance uid

based on ideal body weight(Adapted rom 2, Level 9)

Ideal bodweight can be estimated based on the ollowing ormula: 72,Level9

Female: 45.5 kg + 0.91(height -152.4) cm

Male: 50.0 kg + 0.91(height -152.4) cm

Recommendation

Encourage adequate oral uid intake. (Grade C)

IV uid is indicated in patients who are vomiting or unable to tolerate

oral uids. (Grade C)

IV uid is also indicated in patients with increasing HCT (indicating

on-going plasma leakage) despite increased oral intake. (Grade C)

Crystalloid is the uid o choice or non shock patients. (Grade C)

7.5.3 Dengue Shock Sndrome (DSS) (DHF Grade III & IV)

Dengue shock syndrome is a medical emergency. Recognition o shock in

its early stage (compensated shock) and prompt uid resuscitation will give

a good clinical outcome.73,Level 2 Reer Table 1 or details. However, ailure to

recognise the compensated shock phase will ultimately lead to decompensated

(hypotensive) shock and a more complicated disease course.

Pulse pressure o < 20 mmHg and systolic pressure < 90 mmHg are late

signs o shock in adults.

All patients with dengue shock should be managed in high dependency

intensive care units. Fluid resuscitation must be initiated promptly

and should not be delayed while waiting or admission to ICU or high

dependency unit.

Following initial resuscitation there maybe recurrent episodes o shock

because capillary leakage can continue or 24-48 hours.

IV uid therapy is the mainstay o treatmentor dengue shock.2, Level 9; 73, Level

2; 74,Level 2To date, only three randomised controlled trials studying dierent

types o uid regime in DSS in children aged rom 5 to 15 years o age

are available.73, Level 2; 74, Level 2;75, Level 2Our recommendations are extrapolated

rom these studies. These studies showed no clear advantage o using any

o the colloids over crystalloids in terms o the overall outcome.However,


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colloids may be preerable as the uid o choice in patients with intractable

shock in the initial resuscitation. Colloids seem to restore the cardiac

index and reduce the level o HCT aster than crystalloids in patients with

intractable shock. 74Level 2 The choice o colloids includes gelatin solution

(e.g. Gelausine) and starch solution (e.g. Voluven).

Principles for uid resuscitationThe volume o initial and subsequent uid resuscitation depends on the

degree o shock and can vary rom 10-20 mL/kg ideal body weight. The

volume and rate o uid replacement should be careully titrated to the

clinical response to maintain an eective circulation while avoiding an over-

replacement.

Improvement in the ollowing parameters indicates adequate uid resuscitation:

Clinical parametersImprovement o general well being/mental state

Warm peripheries

Capillary refll time


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Reer to the Algorithm A and Algorithm B or details.

Recommendation

For initial resuscitation

Crystalloids are the uid o choice in patients with DSS.(Grade A)

Colloids may be preerred as the uid o choice in patients withsevere shock. (Grade B)

When two cycles o initial resuscitation with crystalloids ail to restore

haemodynamic stability, colloids should be considered.(Grade C)


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HCT = haematocrit

1GXM: require first stage cross match or emergency O

2fresh blood: less than 5 days

IV crystalloid 5 - 7ml/kg/hr for

1 - 2 hours, then:

oreduce to 3 - 5 ml/kg/hr for

2 - 4 hours;

o reduce to 2 - 3 ml/kg/hr for

2 - 4 hours

If patient continues to improve,fluid can be further reduced

Monitor HCT 4 - 6 hourly

If the patient is not stable,

act according to HCT levels:

o if HCT increases, consider

bolus fluid administration or

increase fluid administrationo if HCT decreases, consider

transfusion with fresh whole

blood

Consider to stop IV fluid at

48 hours of plasma leakage / defervescence

COMPENSATED SHOCK

(systolic pressure maintained but has signs of reduced perfusion) Fluid resuscitation with isotonic crystalloid 5 - 10 ml/kg/hr over 1 hour

FBC, HCT, before and after fluid resuscitation, BUSEC, LFT, RBS, PT/APTT, Lactate/HCO3, GXM1

Check HCT

Administer 2nd bolusof fluid

10-20 ml/kg/hr for 1 hr

Consider significantoccult/overt bleed

Initiate transfusion with

fresh blood2(whole blood/packed cell)

If patient improves,

reduce to 7-10 ml/kg/hr

for 1 - 2 hours

Then reduce further

IMPROVEMENT

IMPROVEMENT

YES

YES NO

NO

or high

ALGORITHM A - FLUID MANAGEMENT IN COMPENSATED SHOCK

REVISEDJULY 2010


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ALGORITHM B - FLUID MANAGEMENT IN DECOMPENSATED SHOCK

Consider to stop IV fluid at48 hours of plasma leakage

/ defervescence

HCT = haematocrit

1GXM: require first stage cross match or emergency O

2fresh blood: less than 5 days

REVISEDJULY 2010


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7.6 MANAGEMENT OF BLEEDING/HAEMOSTASIS7.6.1 Haemostatic Abnormalities in Dengue InectionThe haemostatic changes that occur in dengue inection are a result oendothelial activation.76 level 9; 77, level 8; 78, level 5 This leads to thrombocytopaeniaand coagulation activation which are an intrinsic part o the disease.76, level9; 77, level 8; 78, level 5

Thrombocytopaenia and coagulation abnormalities do not reliably predictbleeding in dengue inection.34, level 6; 33, level 1; 36, level 8

Markers o endothelial activation such as elevated levels o thrombomodulin,tissue actor and Von Willebrand actor are more oten seen in severedengue.79, level 6; 80, level 6 Increased levels o these proteins may promotemicrovascular thrombosis and end-organ damage.81, level 9

7.6.2 How to Recognise Signifcant Occult Bleeding?Bleeding is considered signifcant when it results in haemodynamicinstability. Bleeding rom the gums or per vagina, epistaxis and petechiaeare common but will usually cease spontaneously and are oten notsignifcant.2, level 9 Signifcant bleeding or disseminated intravascularcoagulation usually occurs ollowing prolonged shock and acidosis.32, level 8

Suspect signifcant occult bleeding in the ollowing situations:

Haematocrit not as high as expected or the degree o shock to be explained by

plasma leakage alone. 32, level 8

A drop in haematocrit without clinical improvement despite adequate uid

replacement (40-60 ml/kg).32, level 8; 66, level 9

Severe metabolic acidosis and end-organ dysunction despite adequate uid

replacement.32, level 8

7.6.3 Management o Bleeding in Dengue

Mild bleeding such as rom the gums, per vagina, epistaxis or petechiae,

usually cease spontaneously and do not require blood transusion.2, level 9

Transusion o blood and blood components in dengue is indicated whenthere is evidence o signifcant bleeding.32, level 8

Transusion o blood in patients with signifcant bleeding

Transused 5-10ml/kg o resh-packed red cells or 10-20 ml/kg o resh

whole blood at an appropriate rate and observe the clinical response.

Consider repeating the blood transusion i there is urther blood loss or no

appropriate rise in HCT ater blood transusion.

Recommendation

Patients with mild bleeding such as rom the gums or per vagina,

epistaxis and petechiae do not require blood transusion. (Grade C)

Blood transusion with whole blood or packed cell (preerably less than 1

week) blood component is indicated in signifcant bleeding. (Grade C)

REVISEDJULY 2010


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7.6.4 Management o Upper Gastrointestinal Bleeding

No studies have looked at the use o proton pump inhibitor in upper GIT

bleeding in dengue.

Endoscopy and endoscopic injection therapy in upper GIT haemorrhage

increases the risk o bleeding and must be avoided.82, Level 7

Generally, most o the GIT bleed will improve ater 48-72 hours o the

deervescence. A persistent bleed beyond this time will require urther

investigation.

Recommendation

Endoscopy and endoscopic injection therapy in upper GIT

haemorrhage should be avoided. (Grade C)

Blood transusion with whole blood or packed cell (as resh as is

available, preerably less than one week old) blood components is

indicated in signifcant bleeding. (Grade C)

7.6.5 The Role o Prophlactic Transusions in Dengue

Prophylactic transusion with platelets and resh rozen plasma do not

produce sustained changes in the coagulation status and platelet count in

patients with DHF/DSS.83,Level 8 ; 84, Level 8

Prophylactic transusion with platelets and resh rozen plasma do not

change or reduce the bleeding outcome in DHF. 83, Level8; 84, Level 8 ; 36, Level 8

Inappropriate transusion o blood components increases the risk o

pulmonary oedema and respiratory embarrassment.83,Level 8

Recommendation

There is no role or prophylactic transusion with platelets and reshrozen plasma in dengue patients. (Grade C)

7.6.6 The Role o Adjunctive Therap in Dengue

There is insufcient evidence to support the use o recombinant activated

actor VII in dengue patients with signifcant bleeding.85, Level 3; 86, Level 9 The

coagulation system is activated in dengue and inusion o activated actor

concentrates may increase the risk o thrombosis.87, Level 9

There is insufcient evidence to support the use o intravenousimmunoglobulin88, Level 3and steroids89, Level 1 in the management o dengue

patients.

However there are anedoctal reports,72, Level 9 that demonstrated a dramatic

response when pulse methylprednisolone and high dose immunoglobulin

G (lgG) was used in the early phase o haemophagocytic syndrome.


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7.7 INTENSIVE CARE MANAGEMENT

The management o DSS in the intensive care unit (ICU) ollows the general

principles o management o any critically ill patient in the ICU. However,

certain aspects which are o particular relevance to the management

o DSS are discussed here. There are several papers reviewing dengue

patients who were admitted to ICU. Several indications or ICU care were

observed as listed in the box below. 10, Level 8, 90, Level 8; 91, Level 8

Indications or reerral to Intensive Care:

1. Recurrent or persistent shock

2. Requirement or respiratory support (non-invasive and invasive ventilation)

3. Signifcant bleeding

4. Encephalopathy or encephalitis

7.7.1 Indications or respirator support (non-invasive and invasive ventilation)

The main objectives o respiratory support are to support pulmonary gas

exchange and to reduce the metabolic cost o breathing.

In general, respiratory support should be considered early in a patients

course o illness and should not be delayed until the need arises. The

decision to initiate respiratory support should be based on clinical

judgement that considers the entire clinical situation.92,Level 9

In patients with metabolic acidosis, respiratory support should be

considered despite the preservation o relatively normal arterial blood pH.

When PaCO2

is higher than expected to compensate or the acidosis, the

patient should be promptly intubated.

Formula to calculate the expected PaCO2

= 1.5 x [HCO3-] + 82 mmHg

In patients with encephalopathy and GCS o


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Formula : MAP ( Mean Arterial Pressure)

= DBP + 1/3 (SBP - DBP)DBP = diastolic blood pressure

SBP = systolic blood pressure

7.7.3 Guide on saet and risk o invasive procedures

a. Central venous catheter (CVC) insertion

Volume resuscitation does not require a CVC i sufcient peripheral

intravenous access can be obtained (e.g. 14- or 16-gauge intravenous

catheters). In act, peripheral intravenous catheterisation may be preerable

because a greater ow rate can be achieved through a shorter catheter,

assuming the catheters are o equal diameter.96, Level 8 When a CVC o 8.5

French or larger (i.e. an introducer) is used, the length o tubing becomes

the rate limiting actor, not the CVC.

There are no studies on dengue patients with regards to invasive

procedures and bleeding risks. In general, thrombocytopaenia and other

bleeding diathesis are relative contraindications to CVC placement as

high emoral, low internal jugular, and subclavian venous punctures are

difcult to compress and coner an increased risk o uncontrolled bleeding.

However, studies have shown that the incidence o bleeding in patients

with coagulopathy varies ( 0 - 15.5% ).97, Level 8; 98, Level 8; 99, Level 8; 100, Level 8; 101,Level 8

When CVC is indicated in dengue patients (e.g. poor peripheral venousaccess, requirement o vasopressors) it should be inserted by an

experienced operator and under ultrasound guidance i available.102, Level 8;

103, Level 1

There are multiple insertion sites to choose rom: emoral vein, external

jugular vein, internal jugular vein, subclavian vein, brachial vein and cephalic

vein. However, because the subclavian vein and artery are not accessible

to direct compression, the subclavian site is least appropriate or a patient

with a bleeding diathesis104, Level 9;105, Level 9

Recommendation

Volume resuscitation does not require a central venous catherisation

(CVC) i sufcient peripheral intravenous access can be obtained.

(Grade C)

When CVC is indicated, it should be inserted by a skilled operator,

preerably under ultrasound guidance i available. (Grade C)

Subclavian vein cannulation should be avoided as ar as possible.(Grade C)


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b. Arterial catheter insertion

Intra-arterial cannulation is useul as it enables continuous arterial pressure

monitoring and repeated arterial blood gas sampling. It has a very low

incidence o bleeding (1.8 2.6%)106,Level 8

Recommendation

An arterial catheter should be inserted in DSS patients who require

intensive monitoring and requent blood taking or investigations.

(Grade C)

c. Gastric tube

I a gastric tube is required, the nasogastric route should be avoided.

Consider orogastric tube as this is less traumatic.

d. Pleural tap and chest drainIntercostal drainage o pleural eusions should be avoided as it can lead to

severe haemorrhage and sudden circulatory collapse.107,Level 9

Recommendation

Intercostal drainage or pleural eusion is not indicated to relieve

respiratory distress. Mechanical ventilation should be considered.

(Grade C)

8. DISCHARGE CRITERIA

The ollowing should be taken into consideration beore discharging a patient.65,

Level 9; 66,level 9

Aebrile or 48 hours

Improved general condition

Improved appetite

Stable haematocrit

Rising platelet count

No dyspnoea or respiratory distress rom pleural eusion or ascites

Resolved bleeding episodes

Resolution/recovery o organ dysunction

9. PREVENTION OF DENGUE TRANSMISSION IN HOSPITALS

Patients are viraemic and hence potentially inectious during the ebrile

phase.108, Level 8; 109,Level 8 There are a ew small studies that demonstrate higherlevels and prolonged duration o viraemia in patients with DHF.110, Level 6; 111, Level 8

There are no scientifc studies that address the efcacy o mosquito

repellents or mosquito netting in reducing dengue transmission in

hospitalised patients. However several community studies have shown

that the use o mosquito netting/screening was efcacious in preventing

transmission o dengue in the community.112, Level 3; 113, Level 8


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Generally, repellent products with higher concentrations o DEET (N,N-

diethyl-m-toluamide) were ound to have longer repellence times.114, Level 8

A consensus dengue guideline advised the use o mosquito netting

or repellent day and night or hospitalised dengue patients to reduce

nosocomial inection.66, Level 9

10. VACCINATION

There is no eective vaccine available or dengue.115, Level 8; 116, Level 9

11. DENGUE IN PREGNANCy

There are very ew studies addressing the management o dengue in

pregnancy. Generally the presentation and clinical course o dengue in

pregnant women is similar to that in non-pregnant individuals. 118, Level 8

117, Level 8; However, the signs and symptoms may be conused with othercomplications o pregnancy such as toxaemia, Haemolysis, Elevated Liver

Enzymes, Low Platelets (HELLP) syndrome.119, Level 9

There are some reports o an increased incidence o prematurity, in-utero

death and abruptio placenta in these women.v 117, Level 8; 120, Level 8

The ollowing physiological changes in pregnancy may make the diagnosis

and assessment o plasma leakage challenging :

Elevation o HCT in dengue is masked by haemodilution due to increasein plasma volume especially in the 2nd and 3rd trimester. Serial HCT

measurement is crucial or disease monitoring in pregnancy.

The detection o third space uid accumulation is difcult due to the

presence o gravid uterus.

Baseline blood pressure is oten lower and pulse pressure wider

Baseline heart rate may be higher.

Management o inected pregnant patients close to delivery :

Risk o bleeding is at its highest during the period o plasma leakage

(critical phase).

I possible, avoid Lower Segment Caesarean Section (LSCS) or induction

o labour during critical phase (plasma leakage).119, Level 9

Procedures/manoeuvres that may provoke or augment labour should be

avoided during this critical phase.

Care or the mother should be provided in a multidisciplinary way in an area

o the hospital where there are trained personnel available to handle labour

and its complications.

The baby should be observed or vertical transmission o dengue ater

delivery.119, Level 9

Recommendation

All pregnant women with suspected dengue inection must be admitted.

(Grade C)


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REFERENCES1 Annual report 2007. Vector Borne Diseases Section, Mnistry o Health, Malaysia

(Unpublished)

2 Dengue hemorrhagic ever: diagnosis, treatment, prevention and control. 2nd

ed. Geneva: World Health Organization;1997. Available at http://w3.who.int/csr/

resources/publications/dengue/024-33.pd.

3 Nimmannitya S. Clinical spectrum and management o dengue haemorrhagic

ever. SoutheastAsianJTropMedPubHlth 1987;18(3):392-7.

4 Gubler DJ. Dengue and Dengue Haemorrhagic Fever. Clinical Microbiology

Review. 1998;11(3):480-96.

5 Kalayanarooj S, Vaughn DW, Nimmannitya S et al. Early clinical and laboratory

indicators o acute dengue illness. 1:JInfectDis. 1997 Aug;176(2):313-21.

6 Balmaseda A, Hammond SN, Perez MA et al. Short report: assessment o

the World Health Organization scheme or classifcation o dengue severity in

Nicaragua. AmJTropMedHyg, 2005 Dec; 73(6): 1059-62

7 Hammond SN, Balmaseda A, Perez L, et al. (2005) Dierences in dengue severity

in inants, children, and adults in a 3-year hospital-based study in Nicaragua.Am

JTropMedHyg. 2005;73: 1063-170.

8 Guzman MG, Alvarez M, Rodrguez R, et al. Fatal dengue hemorrhagic ever in

Cuba, 1997. IntJInfectDis 1999; 3:1305.

9 Rigau-Perez JG, Lauer MK. Dengue-related deaths in Puerto Rico, 1992-1996:

diagnosis and clinical warning signs. ClinInfectDis. 2006 May 1;42(9):1241-6.

10 Ong A, Sandar M, Chen MI, Sin LY. Fatal dengue haemorrhagic ever in adults

during a dengue epidemic in Singapore. International Journal of Infectious

Diseases. 2007 May;11(3):263-7.

11 Wichmann O, Hongsiriwon S, Bowonwatanuwong C, et al. Risk actors and

clinical eatures associated with severe dengue inection in adults and childrenduring the 2001 epidemic in Chonburi, Thailand. TropMed Int Health. 2004

Sep;9(9):1022-9.

12 Yip WCL. Dengue Haemorrhagic Fever: Current Approaches to Management.

Medical Progress October 1980.

13 Cohen SN, Halstead SB. Shock associated with dengue inection. I. Clinical and

physiologic maniestations o dengue hemorrhagic ever in Thailand, 1964. J

Pediat 1966; 68:448-56.

14 Pongpanich B. Pathogenetic mechanism in dengue hemorrhagic ever: Report o

an international collaborative study.BullWorldHlth.1973; 48:117.

15 Ganong WF. Cardiovascular homeostasis in health and disease. In: Review o

Medical Physiology. 22nd Edition. London: McGraw-Hill; 2005:p.630-46.

16 Bhamarapravati N, Tuchinda P, Boonyapaknavik V. Pathology o Thailand

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17 Sahaphong S, Riengrojpitak S, Bhamarapravati N, et.al. Electron microscopicstudy o the vascular endothelial cell in dengue haemorrhagic ever. SoutheastAsianJTropMedPublicHealth 1980;11:194.

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Documents

CPG 2010- Management of Dengue Infection in Adults (Revised 2nd Ed 2010) (1)