Dengue fever medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Currently, no effective antiviral agents are available to treat symptomatic dengue virus infection, and management remains supportive with emphasis on judicious fluid administration with oral rehydration solution or intravenous fluids. Acetyl-salicylic (aspirin) derivatives and other non-steroidal anti-inflammatory drugs should be avoided because of their potential to increase the risk of bleeding. Patients who have no complications and are able to tolerate oral fluids may be managed at home or as an outpatient. Development of any warning signs suggests the need for intravenous fluid therapy and hospitalization. If the condition progresses to the Dengue shock syndrome, restoration of plasma volume with fluid boluses and/or blood transfusion is required to maintain adequate tissue perfusion.

Antimicrobial Regimen

  • 1. Patients who may be sent home
  • These are patients who are able to tolerate adequate volumes of oral fluids and pass urine at least once every six hours, and do not have any of the warning signs, particularly when fever subsides
  • Patients who are sent home should be monitored daily by health care providers for temperature pattern, volume of fluid intake and losses, urine output (volume and frequency), warning signs, signs of plasma leakage and bleeding, haematocrit, and white blood cell and platelet counts
  • 2. Ambulatory patients with stable haematocrit can be sent home
  • Encourage oral intake of oral rehydration solution (ORS), fruit juice and other fluids containing electrolytes and sugar to replace losses from fever and vomiting
  • Give Paracetamol for high fever if the patient is uncomfortable. The interval of paracetamol dosing should not be less than six hours. Tepid sponge if the patient still has high fever
  • Should be brought to hospital immediately if any of the following occur: no clinical improvement, deterioration around the time of defervescence, severe abdominal pain, persistent vomiting, cold and clammy extremities, lethargy or irritability/restlessness, bleeding (e.g. black stools or coffee-ground vomiting), not passing urine for more than 4–6 hours
  • 3. Patients who should be referred for in-hospital management
  • Patients may need to be admitted to a secondary health care centre for close observation, particularly as they approach the critical phase. These include patients with warning signs (Abdominal pain or tenderness, Persistent vomiting, Clinical fluid accumulation, Mucosal bleed, Lethargy, restlessness, Liver enlargment >2cm, Laboratory:increase in HCT concurrent with rapid decrease in platelet count), those with co-existing conditions that may make dengue or its management more complicated (such as pregnancy, infancy, old age, obesity, diabetes mellitus, renal failure, chronic haemolytic diseases), and those with certain social circumstances (such as living alone, or living far from a health facility without reliable means of transport)
  • 3.1 With warning signs
  • Obtain a reference haematocrit before fluid therapy. Give only isotonic solutions such as 0.9% saline, Ringer’s lactate, or Hartmann’s solution. Start with 5–7 ml/ kg/hour for 1–2 hours, then reduce to 3–5 ml/kg/hr for 2–4 hours, and then reduce to 2–3 ml/kg/hr or less according to the clinical response
  • Reassess the clinical status and repeat the haematocrit. If the haematocrit remains the same or rises only minimally, continue with the same rate (2–3 ml/kg/hr) for another 2–4 hours. If the vital signs are worsening and haematocrit is rising rapidly, increase the rate to 5–10 ml/kg/hour for 1–2 hours. Reassess the clinical status, repeat the haematocrit and review fluid infusion rates accordingly
  • Give the minimum intravenous fluid volume required to maintain good perfusion and urine output of about 0.5 ml/kg/hr. Intravenous fluids are usually needed for only 24–48 hours. Reduce intravenous fluids gradually when the rate of plasma leakage decreases towards the end of the critical phase. This is indicated by urine output and/or oral fluid intake that is/are adequate, or haematocrit decreasing below the baseline value in a stable patient
  • Patients with warning signs should be monitored by health care providers until the period of risk is over. A detailed fluid balance should be maintained. Parameters that should be monitored include vital signs and peripheral perfusion (1–4 hourly until the patient is out of the critical phase), urine output (4–6 hourly), haematocrit (before and after fluid replacement, then 6–12 hourly), blood glucose, and other organ functions (such as renal profile, liver profile, coagulation profile, as indicated)
  • 3.2 Without warning signs
  • Encourage oral fluids. If not tolerated, start intravenous fluid therapy of 0.9% saline or Ringer’s lactate with or without dextrose at maintenance rate. For obese and overweight patients, use the ideal body weight for calculation of fluid infusion. Patients may be able to take oral fluids after a few hours of intravenous fluid therapy. Thus, it is necessary to revise the fluid infusion frequently. Give the minimum volume required to maintain good perfusion and urine output. Intravenous fluids are usually needed only for 24–48 hours
  • Patients should be monitored by health care providers for temperature pattern, volume of fluid intake and losses, urine output (volume and frequency), warning signs, haematocrit, and white blood cell and platelet counts. Other laboratory tests (such as liver and renal functions tests) can be done, depending on the clinical picture and the facilities of the hospital or health centre
  • 4. Severe dengue
  • Severe dengue: Severe plasma leakage leading to dengue shock and/or fluid accumulation with respiratory distress; severe haemorrhages; severe organ impairment (hepatic damage, renal impairment, cardiomyopathy, encephalopathy or encephalitis)
  • 4.1 Treatment of shock
  • 4.1.1 Compensated shock
  • Start intravenous fluid resuscitation with isotonic crystalloid solutions at 5–10 ml/kg/hour over one hour. Then reassess the patient’s condition (vital signs, capillary refill time, haematocrit, urine output). The next steps depend on the situation
  • If the patient’s condition improves, intravenous fluids should be gradually reduced to 5–7 ml/kg/hr for 1–2 hours, then to 3–5 ml/kg/hr for 2–4 hours, then to 2–3 ml/kg/hr, and then further depending on haemodynamic status, which can be maintained for up to 24–48 hours
  • If vital signs are still unstable (i.e. shock persists), check the haematocrit after the first bolus. If the haematocrit increases or is still high (>50%), repeat a second bolus of crystalloid solution at 10–20 ml/kg/hr for one hour. After this second bolus, if there is improvement, reduce the rate to 7–10 ml/ kg/hr for 1–2 hours, and then continue to reduce as above. If haematocrit decreases compared to the initial reference haematocrit (<40% in children and adult females, <45% in adult males), this indicates bleeding and the need to cross-match and transfuse blood as soon as possible
  • Further boluses of crystalloid or colloidal solutions may need to be given during the next 24–48 hours
  • 4.1.2 Hypotensive shock
  • Initiate intravenous fluid resuscitation with crystalloid or colloid solution (if available) at 20 ml/kg as a bolus given over 15 minutes to bring the patient out of shock as quickly as possible
  • If the patient’s condition improves, give a crystalloid/colloid infusion of 10 ml/kg/hr for one hour. Then continue with crystalloid infusion and gradually reduce to 5–7 ml/kg/hr for 1–2 hours, then to 3–5 ml/kg/hr for 2–4 hours, and then to 2–3 ml/kg/hr or less, which can be maintained for up to 24–48 hours
  • If vital signs are still unstable (i.e. shock persists), review the haematocrit obtained before the first bolus. If the haematocrit was low (<40% in children and adult females, <45% in adult males), this indicates bleeding and the need to cross- match and transfuse blood as soon as possible (see treatment for haemorrhagic complications)
  • If the haematocrit was high compared to the baseline value (if not available, use population baseline), change intravenous fluids to colloid solutions at 10–20 ml/kg as a second bolus over 30 minutes to one hour. After the second bolus, reassess the patient. If the condition improves, reduce the rate to 7–10 ml/kg/hr for 1–2 hours, then change back to crystalloid solution and reduce the rate of infusion as mentioned above. If the condition is still unstable, repeat the haematocrit after the second bolus
  • If the haematocrit decreases compared to the previous value (<40% in children and adult females, less than 45% in adult males), this indicates bleeding and the need to cross-match and transfuse blood as soon as possible (see treatment for haemorrhagic complications). If the haematocrit increases compared to the previous value or remains very high ( more than 50%), continue colloid solutions at 10–20 ml/kg as a third bolus over one hour. After this dose, reduce the rate to 7–10 ml/kg/hr for 1–2 hours, then change back to crystalloid solution and reduce the rate of infusion as mentioned above when the patient’s condition improves
  • Further boluses of fluids may need to be given during the next 24 hours. The rate and volume of each bolus infusion should be titrated to the clinical response. Patients with severe dengue should be admitted to the high-dependency or intensive care area
  • 4.2 Treatment of haemorrhagic complications
  • Blood transfusion required
  • Give 5–10ml/kg of fresh-packed red cells or 10–20 ml/kg of fresh whole blood at an appropriate rate and observe the clinical response. It is important that fresh whole blood or fresh red cells are given. Oxygen delivery at tissue level is optimal with high levels of 2,3 di-phosphoglycerate (2,3 DPG). Stored blood loses 2,3 DPG, low levels of which impede the oxygen-releasing capacity of haemoglobin, resulting in functional tissue hypoxia. A good clinical response includes improving haemodynamic status and acid-base balance
  • Consider repeating the blood transfusion if there is further blood loss or no appropriate rise in haematocrit after blood transfusion. There is little evidence to support the practice of transfusing platelet concentrates and/or fresh-frozen plasma for severe bleeding. It is being practised when massive bleeding can not be managed with just fresh whole blood/fresh-packed cells, but it may exacerbate the fluid overload
  • Great care should be taken when inserting a naso-gastric tube which may cause severe haemorrhage and may block the airway. A lubricated oro-gastric tube may minimize the trauma during insertion. Insertion of central venous catheters should be done with ultra-sound guidance or by a very experienced person
  • 5. Treatment of complications and other areas of treatment
  • 5.1 Fluid overload
  • Oxygen therapy should be given immediately
  • When the following signs are present, intravenous fluids should be discontinued or reduced to the minimum rate necessary to maintain euglycaemia
  • signs of cessation of plasma leakage; stable blood pressure, pulse and peripheral perfusion; haematocrit decreases in the presence of a good pulse volume; afebrile for more than 24–48 days (without the use of antipyretics); resolving bowel/abdominal symptoms; improving urine output
  • The management of fluid overload varies according to the phase of the disease and the patient’s haemodynamic status. If the patient has stable haemodynamic status and is out of the critical phase (more than 24–48 hours of defervescence), stop intravenous fluids but continue close monitoring. If necessary, give oral or intravenous furosemide 0.1–0.5 mg/kg/dose once or twice daily, or a continuous infusion of furosemide 0.1 mg/kg/hour. Monitor serum potassium and correct the ensuing hypokalaemia
  • If the patient has stable haemodynamic status but is still within the critical phase, reduce the intravenous fluid accordingly. Avoid diuretics during the plasma leakage phase because they may lead to intravascular volume depletion
  • Patients who remain in shock with low or normal haematocrit levels but show signs of fluid overload may have occult haemorrhage. Further infusion of large volumes of intravenous fluids will lead only to a poor outcome. Careful fresh whole blood transfusion should be initiated as soon as possible. If the patient remains in shock and the haematocrit is elevated, repeated small boluses of a colloid solution may help
  • 5.2 Other complications of dengue
  • Both hyperglycaemia and hypoglycaemia may occur, even in the absence of diabetes mellitus and/or hypoglycaemic agents. Electrolyte and acid-base imbalances are also common observations in severe dengue and are probably related to gastrointestinal losses through vomiting and diarrhoea or to the use of hypotonic solutions for resuscitation and correction of dehydration. Hyponatraemia, hypokalaemia, hyperkalaemia, serum calcium imbalances and metabolic acidosis (sodium bicarbonate for metabolic acidosis is not recommended for pH ≥ 7.15) can occur. One should also be alert for co-infections and nosocomial infections.
  • 5.3 Supportive care and adjuvant therapy
  • renal replacement therapy, with a preference to continuous veno-venous haemodialysis (CWH), since peritoneal dialysis has a risk of bleeding;
  • vasopressor and inotropic therapies as temporary measures to prevent life- threatening hypotension in dengue shock and during induction for intubation, while correction of intravascular volume is being vigorously carried out;
  • further treatment of organ impairment, such as severe hepatic involvement or encephalopathy or encephalitis;
  • further treatment of cardiac abnormalities, such as conduction abnormalities, may occur (the latter usually not requiring interventions)

References

  1. LastName, FirstName (2009). Dengue guidelines for diagnosis, treatment, prevention, and control. Geneva: TDR World Health Organization. ISBN 9789241547871.

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