Dengue/DHF

Regional Guidelines on Dengue/DHF Prevention and Control ( Regional Publication 29/1999 )

Clinical Management of DF/DHF

Effective case management of DF/DHF requires well-trained physicians and nurses, modern state-of-the-art and reliable laboratory facilities, functioning pharmacies and adequate blood supply systems. Early diagnosis of the disease and admission of patients to hospital are therefore important in order to reduce case fatality rates. Depending upon the severity of infection, three disease entities – DF, DHF and DSS – are recognized. The treatment of each of these is discussed below.

4.1 Dengue Fever

The management of DF is symptomatic and supportive.

     Bed rest is advisable during the acute febrile phase.

     Antipyretics or sponging are required to keep the body temperature below 40oC. Aspirin should be avoided since it may cause gastritis, bleeding and acidosis; paracetamol is preferable.

     Analgesics or mild sedatives may be required for patients with severe pain.

     Oral fluids and electrolyte therapy are recommended for patients with excessive sweating or vomiting.

In DHF-endemic areas, patients should be monitored until after they become afebrile and after platelet counts and haematocrit determinations are normal. 

4.2 Dengue Haemorrhagic Fever/Dengue Shock Syndrome

     General considerations

The major pathophysiologic hallmarks that distinguish DHF/DSS from DF and other diseases are abnormal haemostasis and increased vascular permeability that lead to leakage of plasma. The clinical features of DHF/DSS are rather stereotyped, with acute onset of high (continuous) fever, haemorrhagic diathesis (most frequently on the skin), hepatomegaly, and circulatory disturbance (in the most severe form as shock). It is thus possible to make an early and yet accurate clinical diagnosis of DHF/DSS before the critical stage or before shock occurs, by using the pattern of clinical presentations together with thrombocytopenia and concurrent haemoconcentration, which represent abnormal haemostasis and plasma leakage respectively.

The prognosis of DHF depends on early recognition of plasma leakage. This can be achieved by frequent monitoring for a drop in the platelet count and a rise in the haematocrit level. The critical period is at the time of defervescence which occurs approximately on or after the third day of illness. A drop in the platelet count to <100,000/mm³ or less than 1-2 platelets per oil-immersion field (average of 10 oil-immersion field counts), usually precedes a rise in haematocrit and may occur before defervescence. A rise in haematocrit of 20% or more (e.g. increase from 35% to 42%) reflects a significant plasma loss and indicates the need for intravenous fluid therapy. Early volume replacement of lost plasma with isotonic salt solution can modify the severity of disease and prevent shock.

In mild to moderate cases of DHF (Grades I and II), intravenous fluid therapy may be given for a period of 12-24 hours at an outpatient clinic. Patients who continue to have elevated haematocrit, platelet counts below 50,000/mm3, or present with any type of spontaneous haemorrhage other than petechiae should be hospitalized. In general, there is no need to hospitalize all patients with suspected DHF, since only about one-third will develop shock.

     Febrile phase

The management of DHF during the febrile phase is similar to that of DF. Antipyretics may be indicated but salicylates should be avoided. It should be noted that antipyretics do not shorten the duration of fever in DHF. Paracetamol is recommended and should be used only to keep the temperature below 39oC. The following dosages are recommended: under-one year old: 60 mg/dose; 1-2 years old: 60-120 mg/dose; 3-6 years old: 120 mg/dose; and 7-12 years old: 240 mg/dose. Patients with hyperpyrexia are at risk of convulsions.

High fever, anorexia and vomiting lead to thirst and dehydration. Therefore, copious amounts of fluids should be given orally, to the extent tolerated. Oral rehydration solutions, such as those used for the treatment of diarrhoeal diseases*  and/or fruit juices are preferable to plain water.

Patients should be closely monitored for the initial signs of shock. The critical period is during the transition from the febrile to the afebrile phase, and usually occurs after the third day. Serial haematocrit determinations are an essential guide for treatment, since they reflect the degree of plasma leakage and the need for intravenous administration of fluids. Haemoconcentration usually precedes the blood pressure and pulse changes. Haematocrit should be determined daily from the third day, until the temperature has remained normal for one or two days. If haematocrit determination is not possible, haemoglobin determination may be carried out as an alternative, but this is less sensitive.

If the WHO oral rehydration solution (ORS) (90 mmol of Na per litre) is to be used in children under two years of age, additional fruit juice or water should be given in the proportion of one volume of fruit juice (or water) for each two volumes of ORS. The WHO oral rehydration solution consists of: 3.5 g sodium chloride, 2.9 g trisodium citrate dihydrate, 1.5 g potassium chloride, and 20.0 g glucose, dissolved in 1 litre of potable water.

     Volume replacement in DHF

Although there is massive plasma leakage, particularly in shock cases, judicious volume replacement is mandatory. The required volume should be charted on a two or three hourly basis or even more frequently in shock cases. The rate of intravenous fluid replacement should be adjusted throughout the 24-48 hour period of leakage by serial haematocrit determinations, with frequent assessments of vital signs and urine output, in order to ensure adequate volume replacement and to avoid over-volume infusion. The volume of fluid replacement should be the minimum that is sufficient to maintain effective circulation during the period of leakage. Excessive volume replacement and continuation after leakage stops will cause massive pleural effusion, ascites, and pulmonary congestion/oedema with respiratory distress when reabsorption of the extravasated plasma occurs in the convalescent stage. In general, the volume required is maintenance plus 5-8% deficit.

Parenteral fluid therapy can be administered in outpatient rehydration units in mild or moderate cases when vomiting produces or threatens to produce dehydration or acidosis or when haemoconcentration is present. The fluid administered to correct dehydration from high fever, anorexia and vomiting is calculated according to the degree of dehydration and electrolyte loss and should have the following composition: 5% glucose in one-half or one-third physiological saline solution (PSS). In the case of acidosis, one-fourth of the total fluids should consist of 0.167 mol/litre of sodium bicarbonate (i.e. three-quarters PSS plus glucose plus one-quarter sodium bicarbonate).

When there is significant haemo-concentration, i.e. haematocrit elevated 20% or more of the baseline value (alternatively, the normal haematocrit value of children in the same age group in the general population may be used to estimate the degree of haemoconcentration), the fluids used for replacement therapy should have a composition similar to plasma. The volume and composition are similar to those used in the treatment of diarrhoea with mild to moderate isotonic dehydration (5-8% deficit).

The necessary volume of replacement fluid is equivalent to the amount of fluids and elecrolytes lost: thus, 10ml/kg should be administered for each 1% of normal body weight lost. Maintenance fluid requirements, calculated according to the Halliday and Segar⁽¹⁸⁾ formula (Table 3) should be added to the replacement fluid. Since the rate of plasma leakage is not constant (it is more rapid when body temperature drops), the volume and rate of intravenous fluid therapy should be adjusted according to the volume and rate of plasma loss. Plasma loss can be monitored by changes in the haematocrit, vital signs or volume of urine output. However, even where there is massive plasma loss, judicious fluid replace-ment is necessary to avoid overhydration.

The schedule shown in Table 3 is recommended as a guideline, and has been calculated for moderate dehydration of about 6% deficit (plus maintenance). In older children and adults who weigh more than 40 kgs, the volume needed for 24 hours should be calculated as twice that required for maintenance.

Patients should be hospitalized and treated immediately if there are any of the following signs and symptoms of shock: restlessness/lethargy; cold extremities and circumoral cyanosis; oliguria; rapid and weak pulse; narrowing pulse pressure (20 mm Hg or less) or hypotension, and a sudden rise of haematocrit to a high level or continuously elevated haematocrit levels despite administration of intravenous fluids.

Table 3. Calculations for Maintenance of Intravenous Fluid Infusion*

* Halliday MA, Segar WE. Maintenance need for water in parenteral fluid therapy. Pediatrics. 1957,19:823.

Type of fluid:

     Crystalloid:

5% dextrose in lactated Ringer’s solution (5% D/RL)
5% dextrose in acetated Ringer’s solution (5% D/RA)
5% dextrose in half strength normal saline solution (5% D/1/2/NSS)
5% dextrose in normal saline solution (5% D/NSS)

     Colloidal:

Dextran 40
Plasma

An example of treatment:

The patient: A two year old child has DHF grade II, with the following presentation:

     High fever for 3 days

     Symptoms worsen on day 4 when temperature drops

     Physical examination findings: tempera-ture 37oC, pulse rate 120 per minute, blood pressure 100/70 mmHg, petechiae and a positive tourniquet test; the liver was tender and enlarged by 2 cm

     Laboratory findings: platelets 0 to 1 per oil-immersion field, haematocrit 45% (baseline 35%)

     Administration of intravenous fluid is indicated because the patient has a more than 20% increase in haematocrit level, and early signs of circulatory disturbance are indicated by a rapid pulse and a generally worsening condition.

The following steps should be taken:

     Calculate the volume of intravenous fluid needed for mild isotonic dehydration (5% deficit) based on a 10-kg body-weight.

     Maintenance fluid: 10 x 100 = 1000ml

     5% deficit, 50ml/kg

     10x50 = 500ml

     Total volume needed: = 1500ml

     Order 500ml of glucose in Ringer’s lactate or Ringer’s acetate (50 g/litre), or glucose in a half-strength physiological saline (50 g/litre) (if the serum sodium level is normal):

Fluid volume per order should not exceed 500 ml, and fluid therapy should not take longer than 6 h
Written orders should state the type of solution and the rate of administration. In this example, the rate is 63 ml per hour, or 21 drops per minute (one ml is equal to 21 drops)

     Follow up vital signs every 1 to 2 h and haematocrit every 3 to 4 h. Periodically record urine output and assessment of the patient’s condition

     Adjust the volume and rate of intravenous fluid according to vital signs, haematocrit and urine output as shown in Box 12(20).

The fluid replacement should be the minimum volume that is sufficient to maintaineffective circulation during the period of leakage (24-48 hours). Excessive replacement will cause respiratory distress (from massive pleural effusion and ascites), pulmonary congestion and oedema.

4.3 Dengue Shock Syndrome

Shock is a medical emergency. Volume replacement is the most important treatment measure, and immediate administration of intravenous fluid to expand plasma volume is essential. Children may go into and out of shock during a 48-hour period. Close observation with good nursing care 24 hours a day is imperative (see Box 12).

     Immediate replacement of plasma

Start initial intravenous fluid therapy with Ringer’s acetate or 5% glucose in normal saline solution at the rate of 10-20 ml/kg body weight per hour. Run fluids as rapidly as possible. Positive pressure may be necessary in cases of profound shock. If shock persists after initial fluid resuscitation with 10-20 ml/kg body weight per hour, colloidal solution plasma or plasma expander (10% Dextran of medium related molecular mass in normal saline solution) should be administered at the rate of 10-20 ml/kg per hour. In most cases, no more than 30 ml per kg of body weight of plasma or Dextran 40 is needed. In cases of persistent shock after adequate initial resuscitation with crystalloid and colloidal solutions, despite a decline in the haematocrit level, significant internal bleeding should be suspected, and fresh whole-blood transfusion is indicated. If the haematocrit level is still above 40%, a small volume of blood (10 ml per kg body weight per hour) is recommended. When improvement in vital signs is apparent, the intravenous infusion rate should be reduced. Thereafter, it should be adjusted according to the haematocrit levels and vital signs.

     Continued replacement of plasma, based on frequent micro-haematocrit determinations

Intravenous administration of fluids should be continued even when there is a definite improvement in the vital signs and the haematocrit has decreased. The rate of fluid replacement should be decreased to 10 ml per kilogram per hour, and readjusted thereafter to the rate of plasma loss, which may continue for 24 to 48 hours. The determination of central venous pressure may also be necessary in the treatment of severe cases of shock that are not easily reversible.

Intravenous administration of fluids should be discontinued when the haematocrit decreases to a stable level, around 40%, and the patient’s appetite returns. Good urinary output indicates that there is sufficient fluid circulating. In general, there is no need to administer fluid therapy for more than 48 hours after the termination of shock. Reabsorption of extravasated plasma occurs 2 to 3 days thereafter (manifested by a further drop in haematocrit after the intravenous administration of fluid has been terminated) and may cause hypervolaemia, pulmonary oedema or heart failure if more fluid is given. It is of the utmost importance that a decrease in the haematocrit in this phase is not interpreted as a sign of internal haemorrhage. Strong pulse and blood pressure (with wide pulse pressure) and diuresis are good vital signs during this reabsorption phase. They rule out the likelihood of gastrointestinal haemorrhage, which is found primarily in the shock phase.

     Other electrolyte and metabolic disturbances that may require specific correction

Hyponatraemia occurs commonly and metabolic acidosis occurs occasionally in DHF/DSS patients. Electrolyte levels and blood gases should be determined periodically in severely ill patients and in those who do not respond as quickly as expected. This will provide an estimate of the magnitude of the electrolyte (sodium) deficit and help determine the presence and degree of acidosis. Acidosis in particular, if unresolved, may lead to disseminated intravascular clotting and to a more complicated course of recovery.

The use of heparin may be indicated in some of these cases, but extreme caution should be exercised when it is administered. In general, early volume replacement and early correction of acidosis with sodium bicarbonate result in a favourable outcome and preclude the need for heparin.

     Sedatives

In some cases, treatment with sedatives is necessary to calm an agitated child. Hepatotoxic drugs should be avoided. Chloral hydrate, administered orally or rectally, is highly recommended at a dosage of 12.5-50 mg per kilogram of body weight (but no more than 1 g) as a single hypnotic dose. Agitation/restlessness that results from poor tissue perfusion often subsides when adequate fluid volume replacement is given.

     Oxygen therapy

Oxygen therapy should be provided for all patients in shock, but it must be remembered that an oxygen mask or tent may lead to increased patient anxiety.

     Blood transfusion

Blood grouping and cross-matching should be carried out as a systematic precaution on every patient in shock, particularly in cases with prolonged shock. Blood transfusion is indicated in cases with significant haemorrhagic manifestations.

It may be difficult to recognize internal haemorrhage if there is haemoconcentration. A decrease in the haematocrit - e.g. from 0.5 (50%) to 0.4 (40%) - without clinical improvement, despite the administration of sufficient fluids, indicates significant internal haemorrhage. Fresh whole blood is preferable and the volume of blood administered should be only enough to raise the red blood cell concentration to normal. Fresh frozen plasma and/or concentrated platelets may be indicated in some cases when disseminated intravascular coagulation causes massive bleeding.

Disseminated intravascular coagulation is common in severe shock, and may play an important role in the development of massive bleeding and lethal shock. The results of haematological tests (e.g. prothrombin time, partial thromboplastin time, and fibrinogen degradation products) should be studied in all patients with shock to monitor the onset and severity of disseminated intravascular coagulation. Results of these tests will determine the prognosis.

     Essential laboratory tests

In addition to serial haematocrit and platelet determinations, the following tests are recommended to evaluate the patient’s status: studies of the serum electrolytes and blood gases; platelet count, prothrombin time, partial thromboplastin time and thrombin time; and liver function tests - serum aspartate aminotransferase [(previously known as serum glutamic oxaloacetic transaminase, (SGOT)], serum alanine aminotransferase [(previously known as serum glutamic pyruvic transaminase (SGPT)], and serum proteins.

     Monitoring and anti-shock therapy

Frequent recording of vital signs and haematocrit determinations are important in evaluating treatment results. If the patient presents some indication of secondary shock, vigorous anti-shock therapy should be instituted promptly. These patients should be under constant and careful observation until there is reasonable assurance that the danger has passed. In practice:

     The pulse, blood pressure, respirations and temperature should be recorded every 15 to 30 minutes or more frequently, until the shock has been overcome.

     Haematocrit levels should be determined every two hours during the first six hours, and later every four hours until stable.l A fluid balance sheet should be kept, recording the type, rate and quantity of fluid administered, in order to determine whether there has been sufficient replacement and correction of fluids and electrolytes. The frequency and volume of urine excreted should also be recorded.

4.4 Criteria for Discharging Patients Hospitalized with DHF/DSS

All of the following six criteria must be met before a patient is discharged:

     Absence of fever for 24 hours without the use of antipyretics and a return of appetite.

     Visible improvement in clinical picture.

     Stable haematocrit.

     Three days after recovery from shock.

     Platelet count greater than 50,000/mm3.

     No respiratory distress from pleural effusion/ascites.

4.5 Management of Unusual Manifestations/Complications

The most frequently encountered unusual manifestations are acute hepatic failure and renal failure (which usually follow prolonged shock) that require specific and appropriate treatment. Early blood transfusion in cases of hepatic encephalopathy or Reye’s-like syndrome has proved to be life saving in a number of cases, as has haemodialysis in renal failure cases.

Some DHF patients present unusual manifestations with signs and symptoms of CNS involvement, such as convulsion and/or coma. This has generally been shown to be encephalopathy, not encephalitis, which may be a result of intracranial haemorrhage or occlusion associated with DIC. In recent years, however, several cases with CNS infections have been documented by virus isolations from the CSF or brain⁽²¹⁾.

4.6 DHF Special Unit

For the purpose of more effective manage-ment, DHF patients should be hospitalized in a semi-intensive care unit that is a mosquito-free area. Paramedical workers or parents can assist in oral fluid therapy and monitor the IV fluid and the general status of the patient. Experience at the Children’s Hospital, Bangkok,⁽¹⁹⁾ where a great number of DHF cases are seen each year, has shown that management without using corticosteroids or any vasopressure drugs, results in a steady decline in mortality in the case of shock cases. The case fatality rate dropped from about 5% in 1971 to 2% in 1984 and 0.2% in 1990. Studies on the use of corticosteroids in treating DSS have shown no benefit. The prognosis of DHF/DSS thus depends on: early diagnosis, early recognition of shock, careful clinical observations, and volume replacement guided by simple laboratory tests⁽²⁰⁾.

4.7 Role of WHO Collaborating Centres

Additional information, practice advice and consultation regarding case management of DF/DHF/DSS can be obtained from the WHO Collaborating Centres (CC) for Case Management of Dengue/DHF/DSS (see Annex 1). The WHO Regional Office for South-East Asia (SEARO) has supported the training of 30 physicians from dengue endemic countries of the Region on clinical management of dengue/DHF/DSS at this CC. SEARO and the WHO CC will provide technical support to dengue-training wards proposed to be established during 1998-99 for clinical management of DF/DHF/DSS in dengue endemic countries of the Region. Also, it is expected that, through networking, it will be possible not ony to standardize the case management of DF/DHF/DSS patients, but also to obtain rapid information on the occurrence of cases which is essential for establishing early warning systems for dengue outbreaks and their management (see Box 13).