Pharmacotherapy of dengue fever including recent guidelines

1. Dr. Arun S
1st Year Post Graduate
Department of Pharmacology
GMC, Ananthapuramu

2. SPECIFIC LEARNING OBJECTIVES
BY THE END OF THE SEMINAR THE POST GRADUATE
STUDENTS WILL BE ABLE TO
1. Define Dengue fever and list out few factors causing the spread of
the fever
2. List out the various manifestations and complications of dengue
3. Describe the non-pharmacological and pharmacological
management of dengue fever
4. Describe the various precautions to be taken in Dengue patients
with co-morbidities
5. List out the vaccines approved by FDA for the prevention of dengue
fever

3. DENGUE FEVER - INTRODUCTION
Flaviviridae

14. Bed rest
Vector control
methods
Mosquito
repellants
Mosquito
nets
Fluids
intake
Patient
education
Maintain
hygiene

15. DENGUE WITHOUT WARNING SIGNS:
PLAN A - OUTPATIENT TREATMENT
• Control high fever - Paracetamol
• Ibuprofen, aspirin, or aspirin containing
drugs not to be given
• Tepid sponging should be done

18.  General management of Dengue Fever (DF):
• Management of dengue fever is symptomatic and supportive.
• Bed rest is advisable during the acute phase.
• Use cold/ tepid sponging to keep temperature below 38.5℃.
• Paracetamol as Antipyretic to lower body temperature is preferable in the
recommended doses.
• Note: In children the dose of oral and IV paracetamol is calculated as per
15 mg/Kg body weight and 10 mg/Kg body weight respectively per dose at
an interval of 6 hrs depending upon fever and body ache.
• Encourage oral intake of at least 5 glasses of other fluids (with electrolytes)
in addition to normal daily intake of plain fluid. Small frequent sips for those
with nausea and anorexia.
• Patients should be monitored for development of complications till 24 to 48
hours after they become afebrile.

19. Fluids to be Taken Fluids to be Avoided
Fruit Juices Commercial carbonated drinks
Coconut Water (cold drinks)
Rice Water Drinks that exceed the isotonic
Barley Water level (5% sugar)
Oral Rehydration Solution
Soup
What should be Done What should not be Done
Adequate bed rest Do not take NSAIDs like aspirin or
steroids.
Adequate fluid intake Do not take combination of paracetamol
with other NSAIDs
Take paracetamol
Tepid Sponging Antibiotics are not necessary
Look for mosquito breeding places in and
around the home and eliminate them

20. DENGUE WITH WARNING SIGNS:
PLAN B - INPATIENT MANAGEMENT
SUSCEPTIBLE PEOPLE:
• Pregnant women
• Infants
• Diabetics
• Old age
• Renal failure
Mainstay Rx - IV FLUIDS

21. Choice of IV Fluid
IV Fluids to be Given IV Fluids to be Avoided
• Use isotonic iso-osmolar solutions
(normal saline, Ringer’s lactate, Balanced
Crystalloid)
• Colloids are preferred if the blood
pressure has to be restored urgently
• 5-7mL/kg/hour for 1-2hrs followed by 3-
5mL/kg/hr for 2-4hrs. Increase the rate if
vital signs worsening.
• Hypotonic solution, e.g.
0.45% saline, even during the febrile
phase.
• Dextrose containing solutions, but may
be used in hypoglycaemia with close
blood glucose monitoring.
Colloids are used in case of-
• Hypotensive shock
• Repeated shock – 2nd or 3rd shock and onwards
• After >20 to 30 ml/kg of crystalloids
• If Hematocrit does not decrease after crystalloid administration in shock. DOSE: Limited to
30 to 50 ml/kg/day

26. The maintenance fluid should be calculated using the Holliday-Segar formula as follows:
Maintenance Fluid Therapy

28. Febrile phase
• Limit IV fluids.
• Early IV therapy may lead to fluid overload especially with non- isotonic IV fluid
Critical phase
• IV fluids are usually required for 24–48 hours
NOTE: For patients who present with shock, IV therapy should be <48 hours
Recovery phase
• IV fluids should be stopped so that extravasated fluids can be reabsorbed
When to start and stop intravenous fluid therapy
Adequate fluid
therapy
Capillary refill < 2 seconds
Normal heart rate
Normal blood pressure
Normal pulse pressure
Urine ≥ 0.5 ml/kg/hr
HCT to normal
Improving acid-base

29. Procedures: NG tube, catheter, endoscopy
Bleeding arrested with
• Desmopressin
• Recombinant activated factor VII/VIII
• Carbazochrome sodium sulfonate (AC -17)
• If bleeding severe enough - platelet or blood
transfusion
Management of Bleeding in Dengue

31. Not FDA approved
Available as capsules and tablets
Mechanism of action:
1. Carbazochrome is an anti-bleeding agent that
increases platelet aggregation and forms a platelet
plug by interacting with α-adrenoreceptors on
surface of platelets .
2. Contraction of endothelial cells changes the shape
of platelets and promotes the release of factors such
as serotonin, ADP, Von Willebrand and platelet
activating factor by platelets that induce
aggregation and platelet adherence.

32.  Indications for platelet transfusion
 Prophylactic platelet transfusion may be given at levels of <10,000/mm3
in the absence of bleeding manifestations.
• (Not the mainstay of treatment in patients with Dengue fever and
no need for prophylactic transfusion even if platelet count
<40,000/mm3)
 Haemorrhage with or without thrombocytopenia.
 Prolonged shock with coagulopathy and abnormal coagulogram.
 In case of systemic bleeding, platelet transfusion may be needed in
addition to red cell transfusion (Whole fresh blood transfusion doesn’t
have any role in managing thrombocytopenia)

33. Indications for blood transfusion
• Loss of blood (overt blood)—10% or more of total blood
volume
• Refractory shock despite adequate fluid administration, and
declining Hematocrit
Rx:
• Replacement volume should be 10 ml/kg body weight at a
time and coagulogram should be done.
• If fluid overload is present, packed red cell transfusion is to
be given.

34. SUPPORTIVE DRUGS USED IN DENGUE FEVER

36. • When considering several randomized studies (Bandara et al, 2018),
most of the beneficial results of usage of steroids were seen with
intravenous usage, with methyl prednisolone, with high doses and with
multiple doses.
• At high concentrations glucocorticoid molecules intercalate into cell
membrane and alter cellular functions resulting in reduced calcium
and sodium cycling across the plasma membranes of immune cells.
• This is thought to contribute to rapid immunosuppression and a
subsequent reduction of the inflammatory process when corticosteroids
are used in high concentration.

38. According to some studies, false reported dengue IgM positive cases (by using RDT kit)
may happen in Covid-19 infected patients.
• Treatment of Dengue-COVID 19 coinfection is very difficult especially in situations like
ARDS, myocarditis and shock state. Individualized approach with risk-benefit ratio
should be taken for severe cases, patients with co-morbidities and those who are at high
risk. There are no such guidelines for combating the co- infections.
TOCILIZUMAB:
Tocilizumab, Antivirals and other supportive management to be continued as per the current
COVID-19 guidelines.

40. FLUIDS IN DENGUE-COVID CO-INFECTION
1. Fluid therapy to be given in co-infection cases depends on the hemodynamic status of
patient and degree of severity.
2. One may follow the fluid chart given above for clinical management of dengue fever for
most co-infection cases.
3. It is only in the presence of SARI with COVID-19 that we need to be careful with
aggressive fluid administration as it may lead to worsening of oxygenation and in such a
scenario IVC guided fluids should be administered (where the point of care facility is
available) with continuous monitoring for worsening oxygenation.
4. Aggressive fluid resuscitation is recommended for COVID-19 patients in shock for
initial resuscitation.

41. LMWH
• LMWH is being used and has been included in the guidelines for the management of
moderate to severe COVID-19 cases as it is associated with increased thrombosis.
• LMWH is indicated in moderate to severe category; however, careful monitoring is
required by D-dimer estimation and when the platelet count falls below 1,00,000/mm3, it
may be withheld based on the clinical condition.
• In any case of coinfection with active bleeding, LMWH needs to be discontinued
immediately.
EXAMPLES:

42. Use of Corticosteroids
• Dexamethasone has recently been shown to be effective in
severe COVID-19 and has been recommended for the
same.
• Usually the course of illness among coinfected patients
may not be affected much, if Dexamethasone is given
after dengue viremic stage i.e.,5/6 days of dengue illness.
• Hence, the use of steroids can be continued as per
COVID-19 management guidelines.

43. DENGUE IN HYPERTENSION
BP of these patient perceived to be normal may infact be low for
these patients.
Recommendations :-
• Dose of antihypertensive drugs should be titrated according to
blood pressure. Target MAP (mean arterial pressure) should be more
than or equal to 65 mm of Hg.
• Diuretics should be avoided in critical phase or
during hemoconcentration.
• Beta blockers should be withdrawn in presence of shock or
heart failure.
• Calcium channel blockers, ACE Inhibitors, ARBs are relatively
safe unless renal function deteriorates.

44. DENGUE IN DIABETICS
Recommendations:
1. If patient is on insulin, dose
adjustment may be considered
according to patient’s CBG.
2. Hold Oral Hypoglycemic Agents in
Dengue Shock Syndrome.
3. Timely referral

46. INTENSIVE CARE MANAGEMENT OF DENGUE FEVER -
PLAN C
-Oxygen therapy
-Fluid management
-Airway management
-Mechanical ventilation
General Supportive Measures Specific Supportive Therapy
-Hematological and coagulation
abnormalities
-Renal, Hepatic, Cardiac, Neurological
support
-Prevention and Treatment of
superinfection/ co-infection
• Severe Dengue
• Dengue shock syndrome
• Dengue haemorrhagic fever
• Expanded Dengue syndrome

47. • No specific treatment.
• Supportive:
1. Fever reduction
Paracetamol 500 - 650mg Q6H not to exceed 4g/day.
2. Fluid management if shock is present:
Crystalloid - NS 10-20mL/kg body weight for 2 cycles.
Consider colloid for 3rd cycle.
3. If occult bleeding is present:
Fresh packed RBC - 5-10mL/kg or Fresh whole blood - 10-20mL/kg
4. Vasopressors (Dopamine, Noradrenaline) may be considered if Mean arterial pressure is less
than 60mmHg
5. Broad spectrum antibiotics if needed.
No indication of termination of pregnancy

50. • Dengvaxia (CYD-TDV) developed by Sanofi Pasteur is a recombinant tetravalent
(four-serotype) live attenuated virus vaccine that was first licensed in Mexico in
December 2015 for use in individuals 9–45 years of age living in endemic areas.
• It is given as a three-dose series on a 0-, 6-, 12-month schedule. Additional dengue
vaccine candidates are in clinical development.
• Dengvaxia demonstrated protection against severe dengue cases in its phase 3
trials conducted in Asia and Latin America. However, there were limitations in its
overall efficacy which was affected by factor like serotype, serostatus at vaccination
(whether the person has had a prior infection or not), region or country and age.

52. TV003/005 VACCINE
• New dengue vaccines TV003/TV005 have been developed by the National Institute
of Allergy and Infectious Diseases. They produce antibodies to all 4 dengue virus
serotypes. In earlier trials, a single dose of either of the vaccines was able to elicit a
robust antibody and cellular immune response.
• A Phase 3 trial of TV003 has begun in January 2016 in Sao Paulo to test how
effective the vaccine is in preventing dengue and to test its safety.
TDV VACCINE:
• Another vaccine developed by Takeda called the Tetravalent Dengue Vaccine
(TDV) has also entered its Phase 3 trials early in 2016 in Latin America and Asia.
• Data from its Phase 1 and Phase 2 trials indicate that it is safe, well tolerated and
immunogenic.
• The Phase 3 trial will check if the vaccine protects individuals at risk for
symptomatic dengue across geography, irrespective of their serostatus.

53. DENGVAXIA
PREVACCINATION
CHECKLIST

55. • Goodman & Gilman's The Pharmacological Basis of Therapeutics - 13th
edition
• Park’s Textbook of Preventive and Social Medicine - 26th Edition
• Harrison's Principles of Internal Medicine - 20th Edition
Web references:
https://www.cdc.gov/dengue
https://www.who.int/publications-detail-redirect/9789241504713
https://nvbdcp.gov.in/index1.php?lang=1&level=1&sublinkid=5776&lid=3690