(Abridged version of ‘Clinical management of Dengue, WHO 2012; Available from: http://whqlibdoc.who.int/publications/2009/9789241547871_eng.pdf)
Overview, differential diagnosis and dengue diagnostics
1.1 Overview and course of dengue illness
Dengue viruses cause symptomatic infections or asymptomatic seroconversion. Symptomatic dengue infection is a systemic and dynamic disease. It has a wide clinical spectrum that includes both severe and
(Figure 1). Due to its dynamic nature, the severity of the disease will usually only be apparent around defervescence i.e. during the transition of the febrile to the afebrile phase, which often coincides with the onset of the critical phase.
Fig. 1. The course of dengue illness
IgM = immunoglobulin M; IgG = immunoglobulin G. Temperature is given in degrees Celsius (°C) Source: adapted from Yip, 1980 (2) by authors.
For a disease that is complex in its manifestations, management is relatively simple, inexpensive and very effective in saving lives, so long as correct and timely interventions are instituted. The key to a good clinical outcome is understanding and being alert to the clinical problems that arise during the different phases of the disease, leading to a rational approach in case management.
Activities (triage and management decisions) at the primary and secondary care levels (where patients are first seen and evaluated) are critical in determining the clinical outcome of dengue. A
1.1.1 Febrile phase
Patients typically develop a
Mild haemorrhagic manifestations such as petechiae and mucosal membrane bleeding (e.g. of the nose and gums) may be seen (3, 5). Easy bruising and bleeding at venepuncture sites is present in some cases. Massive vaginal bleeding (in women of childbearing age) and gastrointestinal bleeding may occur during this phase although this is not common (5). The liver may be enlarged and tender after a few days of fever
(3). The earliest abnormality in the full blood count is a progressive decrease in total white cell
count, which should alert the physician to a high probability of dengue (3). In addition to these somatic symptoms, with the onset of fever patients may suffer an acute and progressive loss in their ability to perform their daily functions such as schooling, work and interpersonal relations (6).
1.1.2 Critical phase
During the transition from the febrile to afebrile phase, patients without an increase in capillary permeability will improve without going through the critical phase. Instead of improving with the subsidence of high fever; patients with increased capillary permeability may manifest with the warning signs, mostly as a result of plasma leakage. The warning signs (summarized in Textbox C) mark the beginning of the critical phase. These patients become worse around the time of defervescence, when the temperature drops to 37.5−38°C or less and remains below this level, usually on days
The degree of haemoconcentration above the baseline haematocrit reflects the severity of plasma leakage; however, this may be reduced by early intravenous fluid therapy. Hence, frequent haematocrit determinations are essential because they signal the need for possible adjustments to intravenous fluid therapy. Pleural effusion and ascites are usually only clinically detectable after intravenous fluid therapy, unless plasma leakage is significant. A right lateral decubitus chest radiograph, ultrasound detection of free fluid in the chest or abdomen, or gall bladder wall oedema may precede clinical detection. In addition to the plasma leakage, haemorrhagic manifestations such as easy bruising and bleeding at venepuncture sites occur frequently. If shock occurs when a critical volume of plasma is lost through leakage, it is often
preceded by warning signs. The body temperature may be subnormal when shock occurs. With profound and/or prolonged shock, hypoperfusion results in metabolic acidosis, progressive organ impairment, and disseminated intravascular coagulation. This in turn can lead to severe haemorrhage causing the haematocrit to decrease in severe shock. Instead of the leukopenia usually seen during this phase of dengue, the total white cell count may increase as a stress response in patients with severe bleeding. In addition, severe organ involvement may develop such as severe hepatitis, encephalitis, myocarditis, and/or severe bleeding, without obvious plasma leakage or shock (9). Some patients progress to the critical phase of plasma leakage and shock before defervescence; in these patients a rising haematocrit and rapid onset of thrombocytopenia or the warning signs, indicate the onset of plasma leakage. Cases of dengue with warning signs will usually recover with intravenous rehydration. Some cases will deteriorate to severe dengue (see Section 1.1.4).
Warning signs of dengue
Warning signs usually precede the manifestations of shock and appear towards the end of the febrile phase, usually between days
1.1.3 Recovery phase
As the patient survives the 24−48 hour critical phase, a gradual reabsorption of extravascular compartment fluid takes place in the following 48−72 hours. General wellbeing improves, appetite returns, gastrointestinal symptoms abate, haemodynamic status stabilizes, and diuresis ensues. Some patients have a confluent erythematous or petechial rash with small areas of normal skin, described as “isles of white in the sea of red” (10). Some may experience generalized pruritus. Bradycardia and electrocardiographic changes are common during this stage. The haematocrit stabilizes or may be lower due to the dilutional effect of reabsorbed fluid. The white blood cell count usually starts to rise soon
after defervescence but the recovery of the platelet count is typically later than that of the white blood cell count. Respiratory distress from massive pleural effusion and ascites, pulmonary oedema or congestive heart failure will occur during the critical and/or recovery phases if excessive intravenous fluids have been administered. Clinical problems during the different phases of dengue are summarized in Table 1.
Table 1. Medical complications seen in the febrile, critical and recovery phases of Dengue
1.1.4 Severe dengue
A case of severe dengue is defined as a suspected dengue patient with one or more of the following (see Section 1.2, Figure 2): (i) severe plasma leakage that leads to shock (dengue shock) and/or fluid accumulation with respiratory distress; (ii) severe bleeding; (iii) severe organ impairment.
188.8.131.52 Severe plasma leakage and dengue shock
Dengue shock syndrome (DSS) is a form of hypovolaemic shock and results from continued vascular permeability and plasma leakage. This usually takes place around defervescence, i.e. on days 4−5 of illness (range of days 3−8), and is often preceded by warning signs. From this point onwards, patients who do not receive prompt intravenous fluid therapy progress rapidly to a state of shock. Dengue shock presents as a physiologic continuum, progressing from asymptomatic capillary leakage to compensated shock to hypotensive shock and ultimately to cardiac arrest (Textbox D). Tachycardia (without fever during defervescence), is an early cardiac response to hypovolaemia. It is important to note that some patients, particularly adolescents and adults do not develop tachycardia even when in shock.
During the initial stage of shock, the compensatory mechanism that maintains a normal systolic BP produces tachycardia, quiet tachypnoea (tachypnoea without increased effort) (11), and peripheral vasoconstriction with reduced skin perfusion (manifested as cold extremities and delayed capillary refill time of > 2 seconds and weak volume peripheral pulses). As peripheral vascular resistance increases, the diastolic pressure rises towards the systolic pressure and the pulse pressure (the difference between the systolic and diastolic pressures) narrows. The patient is considered to have compensated shock if the systolic pressure is maintained at the normal or slightly above normal range but the pulse pressure is ≤ 20 mmHg in children (e.g. 100/85 mmHg) or if they have signs of poor capillary perfusion (cold extremities, delayed capillary refill, or tachycardia). In adults, a pulse pressure of ≤ 20 mmHg may indicate more severe shock. Compensated metabolic acidosis is observed when the pH is normal with low carbon dioxide tension and a low bicarbonate level. Patients who have dengue and are in compensated shock often remain conscious and lucid. The inexperienced physician may measure a normal systolic pressure and a normal pulse oximetry (SpO2
Worsening hypovolaemic shock manifests as increasing tachycardia and peripheral vasoconstriction. Not only are the extremities cold and cyanosed but the limbs become mottled, cold and clammy. By this stage the breathing becomes more rapid and increases in depth − a compensation for the metabolic acidosis (Kussmaul’s breathing). Finally, there is decompensation, both systolic and diastolic BPs disappear suddenly and dramatically, and the patient is said to have hypotensive or decompensated shock. At this time the peripheral pulses disappear while the central pulse (femoral) will be weak. Hypotension develops when physiologic attempts to maintain systolic BP and perfusion are no longer effective. One key clinical sign of this deterioration is a change in mental state as brain perfusion declines. The patient becomes restless, confused and extremely lethargic.
Seizures may occur and agitation may alternate with lethargy. On the other hand, children and young adults have been known to have a clear mental status even in profound shock. Adults have been known to be able to work until the stage of profound shock is reached. The failure of infants and children to recognize, focus or make eye contact with parents may be an early ominous sign of cortical hypoperfusion, as is the failure to respond to painful stimuli such as venepuncture. Parents may be the first to recognize these signs −but they may be unable to describe them, other than to say something is wrong. Listen to parents! Hypotension is a late finding and signals an imminent total cardiorespiratory collapse.
Prolonged hypotensive shock and hypoxia lead to severe metabolic acidosis, multiple organ failure and an extremely difficult clinical course (12) (Textbox D). It may take a few hours for patients to progress from warning signs to compensated shock and another few hours for compensated shock to progress to hypotensive shock, but only minutes for hypotensive shock to progress to cardiorespiratory collapse and cardiac arrest.
Hypotension is associated with prolonged shock which is often complicated by major bleeding (12). Patients with severe dengue have varying degrees of coagulation abnormalities, but these are usually not sufficient to cause major bleeding (13). When major bleeding does occur, it is almost always associated with profound shock since this, in combination with thrombocytopenia, hypoxia and acidosis, can lead to multiple organ failure and advanced disseminated intravascular coagulation.
Massive bleeding may occur without prolonged shock in instances when acetylsalicylic acid (aspirin), ibuprofen, or corticosteroids have been taken. Bleeding may occur in patients with previous peptic or duodenal ulcers (14, 15). Acute liver and renal failure and encephalopathy may be present in severe shock; these have been described even in the absence of severe plasma leakage or shock
1.2 Dengue case classification
Changes in the epidemiology of dengue, especially with an increasing number of cases in adults (with and without
1.2.1 Development of the revised dengue case classification
The development of the revised dengue case classification into dengue (with or without warning signs), and severe dengue is based on several different steps and studies:
1.There have been many reports of difficulties in the use of the previous classification
2.A further set of studies (5), comparing existing national, regional and international guidelines for dengue prevention and control, concluded that the dengue case classification existing at the time was being used inconsistently. Many countries report dengue according to
Fig. 2. Dengue case classification by severity
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CNS = central nervous system; DSS =dengue shock syndrome; HCT = haematocrit
3.A prospective clinical multicentre study across
4.Expert consensus groups meeting in Latin America (Havana, Cuba, 2007),
Lumpur, Malaysia, 2007) and at WHO headquarters (Geneva,Switzerland, 2008) agreed that “dengue is one disease entity with different clinical presentations and often with unpredictable clinical evolution and outcome”.
5.The updated model for classifying dengue has been suggested by the Geneva based expert group and a set of studies has been initiated comparing this model to the previous case classification in terms of applicability and
6.Based on current experience it can be concluded that classification into levels of severity is highly likely to be of practical use. First, to aid the clinicians’ decisions about where, and how intensively, the patient should be observed and treated (i.e. for triage, which is particularly useful in outbreaks). Second, for more consistent reporting in national and international surveillance systems, and as an
7.Since many countries have started to use the newly suggested model, this handbook adopts the distinction between dengue and severe dengue.
1.2.3 Differential diagnoses of dengue
A number of infectious and non infectious diseases mimic dengue and severe dengue. It is thus necessary for clinicians to be familiar with the epidemiological characteristics of febrile diseases in the locality. Clinical manifestations associated with fever, epidemiological information and virological tests (if available) are particularly useful in patients with acute undifferentiated fever (1, 2). Conditions that present with an
Primary infection with HIV may mimic dengue with high fever, malaise, rash and generalized adenopathies (8). Splenomegaly and prolonged fever should prompt the consideration of malaria and typhoid in the differential diagnoses. Fever, malaise, vomiting, liver enlargement and elevated liver enzymes may be misdiagnosed as infectious hepatitis, and
Sepsis and meningococcal disease should be considered in shock patients because of the need for urgent treatment with specific antibiotics. Common symptoms and signs with dengue cases are fever, rash, petechiae, bleedings and shock associated with leucopenia (particularly in severe
usually high, although it could be subnormal in the late stages. Bounding pulses with warm extremities are present in early septic shock. In dengue patients, shock usually occurs after defervescence; hence
the temperature is often subnormal or normal, pulse volume is small, and pulse pressure is narrowed with the patient having cold extremities. Clinical and radiographic signs of plasma leakage and progressive haemoconcentration in severe dengue cases are useful distinguishing features. Another helpful tool to differentiate dengue from these other diseases is to determine the sequence of signs and symptoms, including warning signs during defervescence that frequently announce severe dengue. Clinical distinction between leptospirosis and dengue may be challenging, particularly when both epidemics are concurrent (14). Delayed antibiotic therapy is associated with mortality in leptospirosis. Jaundice is more often associated with leptospirosis, but ocular pain, arthralgia and diarrhoea could be present as well (15). Leptospirosis is frequently associated with professional activity (e.g. working with garbage or in agriculture) or with a history of certain pastimes (e.g. trekking to waterfalls or playing water sports). Pulmonary haemorrhage is a particular form of leptospirosis without jaundice that has some common signs and symptoms with severe dengue; these include fever, thrombocytopenia, shock and massive bleeding in the lungs (16). Pulmonary haemorrhage is uncommon in dengue; evidence of plasma leak such as pleural effusion or ascites would suggest the diagnosis of dengue.
Leukopenia and thrombocytopenia, with or without bleeding, may be clinical manifestations of infectious diseases such as malaria, leptospirosis, typhoid, typhus, bacterial sepsis and acute
Another misdiagnosis is acute (alithiasis) cholecystitis, with the abdominal ultrasonograph showing thickening/oedema of the wall of the gallbladder. This is associated with pain in the subhepatic region, mainly during defervescence. Plasma leakage, not inflammation, is responsible for these clinical features. Patients who underwent surgery as a result of misdiagnosis with an acute surgical abdominal condition have been found to have lifethreatening bleedings; some went on to die. Failure to recognize severe abdominal pain as a warning sign that heralds severe dengue has led to the misdiagnosis of renal lithiasis and delayed intravenous fluid treatment for dengue shock. A differentiating feature of an acute surgical abdomen and the severe abdominal pain of dengue shock is that the abdomen in dengue shock is soft and the pain subsides with fluid resuscitation. Other medical emergencies presenting with intense and continuous abdominal pain include diabetic ketoacidosis, renal failure and lactic acidosis. Again, evidence of plasma leakage (especially after intravenous fluid therapy), thrombocytopenia and bleeding tendencies help to distinguish dengue from other medical or surgical conditions.
The group of viral haemorrhagic fever diseases have bleeding, thrombocytopenia and shock in common. All have the monocyte/macrophage as the target cell (19). These diseases are present in different geographic areas, have different vectors (Table 2), have causative agents that belong to different viral families
to the respective diagnosis.
Yellow fever (YF) is now considered a
classic description of YF covers two phases: the febrile phase and the toxic phase. During the toxic phase, liver damage causing jaundice, renal insufficiency and central nervous system impairment are life- threatening characteristics.
The disease in adults has been associated with high mortality, a relatively short duration, symptoms such as headache, back pain, fever, vomiting and nausea, jaundice, haemorrhages and unconsciousness (23).
Severe dengue with noncardiogenic pulmonary oedema (fluid overload) and pulmonary distress has clinical signs common to the Hantavirus pulmonary syndrome (HPS). In severe dengue, and not in HPS, the pulmonary oedema is usually preceded by prolonged or recurrent shock, associated with bleedings in the lung and other sites, together with signs of plasma leakage and fluid overload. The initial picture of HPS is very similar to that of influenza, with fever, myalgia, vomiting and cough associated with dyspnoea at the end of the first week, and leukocytosis, neutrophilia, thrombocytopenia and elevated haematocrits (24). Children with HPS may have severe abdominal pain and liver enlargement, but bleeding is not frequent and they do not present with pulmonary haemorrhage, but with interstitial and alveolar oedema (25).
1.3 Dengue diagnostics for clinicians
The objectives of dengue laboratory diagnosis are (i) to confirm the clinical diagnosis and (ii) to provide information for epidemiological surveillance. Laboratory diagnosis is not necessary for clinical management except in atypical cases or when carrying out differential diagnosis with other infectious diseases.Laboratory diagnosis of dengue is made by detecting the virus and/or any of its components (infective virus, virus genome, dengue antigen) or by investigating the serological responses present after infection (specifically IgM and IgG levels) (Table 3)
Table 3. Dengue diagnostics and sample characteristics
IgG = mmunoglobulin G; IgM = immunoglobulin M; NS1 Ag =
Dengue viruses are RNA viruses belonging to the family flaviviridae, genus flavivirus. The four dengue viruses
Three main aspects should be considered for an adequate dengue diagnosis: serological markers in relation to the time of dengue infection;
to clinical illness;
Virological and serological markers in relation to time of dengue infection (Figure 3)
An incubation period of
In a primary infection (i.e. when an individual is infected for the first time with a flavivirus), viraemia develops from
slowly increasing but low levels of
Type of dengue diagnostic method in relation to time of clinical illness
The diagnostic method to confirm an acute infection depends on the time of clinical illness: the febrile phase is coincident with the presence of viraemia, some viral components and replication products in blood; the critical and convalescent phases coincide with the development of antibodies, as summarized in Table 3.
Febrile phase (day 1 to days
The infective virus can be isolated in serum by inoculation in tissue culture (mosquito cell cultures) and mosquitoes. This method allows for identification of the viral serotype. Virus genome detection using reverse transcriptase polymerase chain reaction
Fig. 3. Virological and serological markers of dengue infection according to time of illness
IgG = immunoglobulin G; IgM = immunoglobulin M
Critical and convalescent phases (after days
Specific IgM is the best marker of a recent dengue infection.
The study of paired sera (acute and convalescent serum samples with the second sample being collected
Characteristics of the clinical sample
Similar to other enveloped viruses, dengue virus is labile and readily inactivated at temperatures above 30°C, so care should be taken during transportation and storage of samples. Serum samples collected during the first 4 days of fever are useful for virus, genome and dengue antigen detection, thus confirming
a dengue infection. Samples should be rapidly transported at 4°C to the laboratory and be processed as soon as possible. Sterile serum without anticoagulant is useful. If specimen delivery cannot be performed in the first
Tissue specimens collected from fatal cases are useful for virus, genome and antigen detection. Liver, spleen and lymph nodes are the tissues of choice (26, 27). Tissue samples should be collected immediately after death and be immediately frozen at
Besides general patient information a summary of clinical and epidemiological data, such as the date of fever onset, method of sample collection and the type of sample, should accompany clinical samples (1). The usefulness of available diagnostic tests depends on the level of health care (see Table 4). At primary- care level, rapid tests for NS1 Ag detection (suggestive of an acute dengue infection) as well as rapid tests for IgM determination (suggestive of a recent infection), are useful. As patients access care independent of the period of infection suffered – some early, some late – a combination of both NS1 Ag and IgM markers is advisable. At district health centres, both
Laboratory confirmation of a dengue case
A diagnosis of dengue infection is confirmed by the detection of the virus, the viral genome or NS1 Ag, or seroconversion of IgM or IgG (from negative to positive IgM/IgG or
2.2 Treatment according to Groups
2.2.1 Group A
These are patients who may be sent home (see the
These patients are able to tolerate adequate volumes of oral fluids, pass urine at least once every six hours and do not have any of the warning signs (particularly when fever subsides). The key to the success of ambulatory (outpatient) management is to give clear, definitive advice on the care that the patient needs to receive at home: i.e. bed rest and frequent oral fluids. Patients with ≥ 3 days of illness should be reviewed daily for disease progression (indicated by decreasing white blood cell and platelet counts and increasing haematocrit, defervescence and warning signs) until they are out of the critical period. Those with stable haematocrit can be sent home but should be advised to return to the nearest hospital immediately if they develop any of the warning signs and to adhere to the following action plan:
intake may reduce the number of hospitalizations (3). Encourage oral intake to replace fluid loss from fever and vomiting. Small amounts of oral fluids should be given frequently for those with nausea and anorexia. The choice of fluids should be based on the local culture: coconut water in some countries, in others rice water or barley water. Oral rehydration solution or soup and fruit juices may be given to prevent electrolyte imbalance. Commercial carbonated drinks that exceed the isotonic level (5% sugar) should be avoided. They may exacerbate hyperglycaemia related to physiological stress from dengue and diabetes mellitus. Sufficient oral fluid intake should result in a urinary frequency of at least 4 to 6 times per day. A record of oral fluid and urine output could be maintained and reviewed daily in the ambulatory setting.
dose is 10 mg/kg/dose, not more than 3−4 times in 24 hours in children and not more than 3 g/day in adults). Sponge with tepid water if the patient still has a high fever. Do not give acetylsalicylic acid (aspirin), ibuprofen or other
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 coffeeground vomiting), shortness of breath, not passing urine for more than 4−6 hours.
Admission during the febrile period should be reserved for those who are unable to manage adequate oral hydration at home, infants, and those with
2.2.2 Group B
These are patients who should be admitted for
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/hour for 2−4 hours, and then reduce to 2−3 ml/kg/hour or less according to the clinical response (see Textboxes H, J and K).
epeat the haematocrit. If the haematocrit remains the same or rises only minimally, continue at the same rate (2−3 ml/kg/hour) for another 2−4 hours. If the vital signs are worsening and the 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.
an urine output of about 0.5 ml/kg/hour. 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 improving, or the haematocrit decreasing below the baseline value in a stable patient.
ine or Ringer’s lactate with or without glucose at the appropriate maintenance rate (Textbox H). Use the ideal body weight for calculation of fluid infusion for obese and overweight patients (Textboxes J and K). 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
output (volume and frequency), warning signs, haematocrit, white blood cell and platelet counts (Textbox K). Depending on the clinical picture and the facilities of the hospital or health centre, other laboratory tests (such as liver and renal functions tests) can also be carried out.
2.2.3 Group C
These are patients with severe dengue who require emergency treatment and urgent referral because they are in the critical phase of the disease and have: fluid accumulation with respiratory distress;
patic damage, renal impairment, cardiomyopathy,encephalopathy or encephalitis).
All patients with severe dengue should be admitted to a hospital with access to blood transfusion facilities. Judicious intravenous fluid resuscitation is the essential and usually sole intervention required. The crystalloid solution should be isotonic and the volume just sufficient to maintain an effective circulation during the period of plasma leakage. Plasma losses should be replaced immediately and rapidly with isotonic crystalloid solution: in the case of hypotensive shock, colloid solution is preferred (Textbox L). If possible, obtain haematocrit levels before and after fluid resuscitation. Continue replacement of further plasma losses to maintain effective circulation for 24−48 hours. For overweight or obese patients, the ideal body weight should be used for calculating fluid infusion rates (see Textboxes J and K). All shock patients should have their blood group taken and a
Fluid resuscitation must be clearly separated from simple fluid administration. This is a strategy in which larger volumes of fluids (e.g. 10−20 ml/kg boluses) are administered for a limited period of time under close supervision, to evaluate the patient’s response and to avoid the development of pulmonary oedema.
These fluids should not contain glucose. The degree of intravascular volume deficit in dengue shock varies. Input is typically much greater than output, and the input/output ratio is of no help in judging fluid resuscitation needs during this period. The goals of fluid resuscitation include:
– i.e. decreasing tachycardia, improving BP and pulse volume, warm and pink extremities, a capillary refill time < 2 seconds;
184.108.40.206 Treatment of shock
The action plan for treating patients with compensated shock is as follows (see algorithms in Figures 5 and 6):
Start intravenous fluid resuscitation with isotonic crystalloid solutions at 5−10 ml/kg/hour over one hour in adults and 10−20 ml/kg/hour over one hour in infants and children. Then reassess the patient’s condition (vital signs, capillary refill time, haematocrit, urine output).
adult patient’s condition improves, intravenous fluids should be gradually reduced to 5−7 ml/kg/hour for 1−2 hours; then 3−5 ml/kg/hour for 2−4 hours and finally 2−3 ml/kg/hour which can be maintained up to 24−48 hours. Consider reducing intravenous fluid earlier if oral fluid intake improves. The total duration of intravenous fluid therapy should not exceed 48 hours.
infant or child improves, intravenous fluids should be reduced to 10 ml/kg/hour for 1−2 hours; then to 7 ml/kg/hour for 2 hours; 5 ml/kg/hour for 4 hours and then to 3 ml/kg/hour, which can be maintained for up to 24−48 hours. Consider reducing intravenous fluid earlier if oral fluid intake improves. The total duration of intravenous fluid therapy should not exceed 48 hours. H and J for a more appropriate estimate of the normal maintenance requirement based on ideal body weight).
vital signs are still unstable (i.e. shock persists), check the haematocrit after the first bolus.
o In adults:
If the haematocrit increases or is still high (e.g. haematocrit > 50%), repeat a second bolus of crystalloid/colloid solution at 10−20 ml/kg/hour for one hour. After this second bolus, if there is improvement continue with crystalloid solution and reduce the rate to 7−10 ml/kg/hour for 1−2 hours, then continue to reduce as above. If haematocrit decreases compared to the initial reference haematocrit (especially if the repeat haematocrit is below the baseline, for example < 35−40% in adult females, < 40−45% in adult males), and the patient still has unstable vital signs, this may indicate bleeding. Look for severe bleeding.
o In infants and children:
If the haematocrit increases or is still high, change to colloid solution at 10−20 ml/kg/hour. After the initial dose, reduce the rate to 10 ml/kg/hour for 1 hour, then reduce to 7 ml/kg/hour. As mentioned above, change to crystalloid when the patient's condition improves.
If the haematocrit decreases compared to the initial reference haematocrit
(especially if the repeat haematocrit is below the baseline, for example, < 35−40%), and the patient still has unstable vital signs, this may indicate bleeding. Look for severe bleeding.
level. A senior staff member should carry out a review to consider blood transfusion. of crystalloid or colloidal solutions may need to be given during the next 24−48 hours.
to Section 2.4.7 for an outline of dengue in infants and children.
Treatment of profound shock (hypotensive; undetectable pulse and BP)
All patients (infants, children and adults) with hypotensive shock should be managed more vigorously. The action plan for treating patients with hypotensive shock is outlined below (also see Textbox D and Figure 7). For all patients (infants, children and adults), initiate intravenous fluid resuscitation with crystalloid or colloid solution at 20 ml/kg as a bolus given over 15−30 minutes to bring the patient out of shock as quickly as possible. Colloids may be the preferred choice if the BP has to be restored urgently, i.e. in those with pulse pressure less than 10 mmHg. Colloids have been shown to restore the cardiac index and reduce the level of haematocrit faster than crystalloids in patients with intractable shock
24−48 hours (Textbox H). Consider reducing intravenous fluid earlier if oral fluid intake and urine output improve. The total duration of intravenous fluid therapy should not exceed 48 hours. o In infants and
children, give colloid infusion of 10 ml/kg/hour for 1 hour. Then continue with crystalloid 10 ml/kg/hour for 1 hour, then to 7.5 ml/kg/hour for 2 hours, to 5 ml/kg/hour for 4 hours and to 3 ml/kg/hour, which can be maintained for up to
still unstable (i.e. shock persists), review the haematocrit obtained before the first bolus. o If the haematocrit was normal or low (<
o 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 1 hour. After the second bolus, reassess the patient. If the condition improves, reduce the rate to 7−10 ml/kg/hour for 1−2 hours, then change back to crystalloid solution and reduce the rate of infusion as mentioned above.
still unstable, repeat the haematocrit after the second bolus. o If the haematocrit decreases compared to the previous value (< 35% in infants,< 40% in children and adult females, < 45% in adult males), this indicates bleeding and the need to
rther 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
o Clinicians who take care of dengue shock infants should remember that an infant with a low baseline haematocrit of 30%, presenting with dengue shock and a haematocrit of 40%, is relatively more haemoconcentrated than another child with a baseline value of 42% and haematocrit of 50% at the time of shock.
Patients with dengue shock should be monitored frequently until the danger period is over. A detailed fluid balance of all inputs and outputs should be maintained. Parameters to be monitored include: alertness and comfort levels, vital signs and peripheral perfusion (every 15−30 minutes until the patient is
out of shock then 1−2 hourly). In general, the higher the fluid infusion rate, the more frequently the
patient should be monitored and reviewed in order to avoid fluid overload while ensuring adequate volume replacement. If previously not detectable, pleural effusion and ascites should be detectable after fluid boluses. Monitor their effects on breathing. If resources are available for blood gas and/or lactate analysis, capillary or venous blood should be sampled for repeated analysis to monitor changes in the circulation during fluid replacement. An arterial line has certain advantages but its placement is hazardous because of the attendant bleeding from failed attempts. The advantage of an arterial line is that in shock states, estimation of BP using a cuff is commonly inaccurate. The use of an indwelling arterial catheter allows for continuous and reproducible BP measurements and frequent blood sampling to base decisions regarding therapy. Monitoring of ECG and pulse oximetry should be available in the intensive care unit. Urine output should be checked regularly (each hour until the patient is out of shock, then every 1−2 hours). A continuous bladder catheter enables close monitoring of urine output. The first urine volume after bladder catheterization should be discarded because the duration in the bladder is unknown. Thereafter, an acceptable urine output would be about 0.5 ml/kg/hour. Haematocrit should be monitored (before and after fluid boluses until stable, then 4−6 hourly). In addition, there should be monitoring of: blood glucose (before fluid resuscitation and repeat as indicated); arterial or venous or capillary blood gases; lactate; total carbon dioxide/bicarbonate (every 30 minutes to 1 hour until stable, then as indicated); and other organ functions (such as renal profile, liver profile, coagulation profile) before resuscitation and as indicated.
Interpretation of haematocrit
The patient’s baseline haematocrit on the first three days of illness is a useful reference point. It is important to note that during fluid therapy, blood samples for haematocrit should be timed such that they are taken before or after the infusion of a known volume of intravenous fluid. The interpretation will be most meaningful if the corresponding haemodynamic state, or response to fluid therapy and the
A rising or persistently high haematocrit together with unstable vital signs (such as narrowed pulse pressure) indicates active plasma leakage and the need for a further bolus of fluid replacement. However, a rising or persistently high haematocrit together with stable haemodynamic status and adequate urine output does not require extra intravenous fluid. In the latter case, continue to monitor closely and it is likely that the haematocrit will start to fall within the next 24 hours as plasma leakage stops. A decrease in haematocrit (for example from 50% to 40% or below the patient’s known baseline) together with unstable vital signs (narrowed pulse pressure, tachycardia, metabolic acidosis and poor urine output), may indicate major haemorrhage. If there is severe haemorrhage, urgent blood transfusion should be given. If there is no clinical sign of bleeding, then a further bolus of
220.127.116.11 When to stop intravenous fluid therapy
Recognizing when to decrease or stop intravenous fluids as part of the treatment of severe dengue is crucial to prevent fluid overload. When any of the following signs are present, intravenous fluids should be reduced or discontinued:
Continuing intravenous fluid therapy beyond the 48 hours of the critical phase will put the patient at risk of pulmonary oedema and other complications such as thrombophlebitis.
18.104.22.168 Treatment of haemorrhagic complications
Mucosal bleeding may occur in any patient with dengue but if the patient remains stable with fluid resuscitation/replacement, this should be considered as a minor issue. The bleeding usually improves rapidly during the recovery phase. In patients with profound thrombocytopenia, ensure strict bed rest and protection from trauma. Do not give intramuscular injections. No evidence exists (from observational studies) that prophylactic platelet transfusions are beneficial in haemodynamically stable patients.
If major bleeding occurs it is usually from the gastrointestinal tract, and/or hypermenorrhoea. Internal bleeding may not become apparent for many hours until the first black stool is passed. Patients at risk of severe bleeding are those who:
erapy; have any form of trauma, including intramuscular injection.
Patients with haemolytic conditions are at risk of acute haemolysis with haemoglobinuria and may require blood transfusion (see Section 2.4.3). Severe and occult bleeding is the most common cause of profound/refractory/prolonged shock, but can be difficult to recognize. This is because bleeding usually occurs after a period of prolonged shock in dengue (9). The preceding plasma leakage causes the haematocrit to rise to very high levels. When bleeding occurs the haematocrit will then drop from this high level and as a result haematocrit levels may not be as low as in the absence of plasma leakage. Even in severe bleeding, the haematocrit remains above the baseline and only drops to normal or low levels after several fluid boluses. Severe bleeding should be recognized in the following situations:
status, regardless of
the haematocrit level;
together with unstable haemodynamic status;
in those with severe abdominal tenderness and distension.
Blood transfusion is
The action plan for the treatment of haemorrhagic complications is as follows:
stop bleeding if the source of bleeding is identified e.g. severe epistaxis may be controlled by nasal adrenaline packing.
5−10 ml/kg of fresh - packed red cells or 10−20 ml/kg of fresh or fairly fresh whole blood (FWB) 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 diphosphoglycerate (2,3 DPG). Stored erythrocytes lose 2,3 DPG, low levels of which impede the
sider repeating the blood transfusion if there is further overt blood loss or no appropriate rise in haematocrit after blood transfusion in an unstable patient. and/or
efficacy have not been studied.
which may cause severe haemorrhage. A lubricated orogastric tube may minimize the trauma during insertion. Insertion of central venous catheters should be done with
indicated in dengue patients with severe bleeding. Unnecessary blood transfusions cause the haematocrit to rise sharply, thus giving a false impression of haemoconcentration and severe plasma leakage leading to unwarranted fluid therapy.
22.214.171.124 Glucose control
Hyperglycaemia and hypoglycaemia may occur in the same patient at different times during the critical phase through the following mechanisms. Hyperglycaemia is the result of a neuroendocrine stress response, occurs in diabetes mellitus and results from large quantities of
Hyperglycaemia is associated with increased morbidity and mortality in critically ill adult and paediatric patients. Hypoglycaemia may cause seizures, mental confusion and unexplained tachycardia.Most cases of hyperglycaemia will resolve with appropriate (isotonic,
is still reduced. However, if hyperglycemia is persistent, undiagnosed diabetes mellitus or impaired glucose tolerance should be considered and intravenous insulin therapy initiated. Subcutaneous insulin should be avoided as absorption is unreliable in the shock state (see Section 2.4.3).
Hypoglycaemia should be treated as an emergency with 0.1−0.5 g/kg of glucose, rather than with a
126.96.36.199 Electrolyte and
Hyponatraemia is a common observation in severe dengue; the underlying mechanism is not fully understood. It could be related to gastrointestinal losses through vomiting and diarrhoea or the use of hypotonic solutions for resuscitation and correction of dehydration. The use of isotonic solutions for resuscitation will prevent and correct this condition. Hyperkalaemia is observed in association with severe metabolic acidosis or acute renal injury. Appropriate volume resuscitation will reverse the metabolic acidosis and the associated hyperkalaemia.
188.8.131.52 Metabolic acidosis
Compensated metabolic acidosis is an early sign of hypovolaemia and shock. Lactic acidosis due to tissue hypoxia and hypoperfusion is the most common cause of metabolic acidosis in dengue shock. Correction of shock and adequate fluid replacement will correct the metabolic acidosis. If metabolic acidosis remains uncorrected by this strategy, one should suspect severe bleeding and check the haematocrit. Transfuse fresh whole blood or fresh packed red cells urgently (see Section 184.108.40.206). Sodium bicarbonate for metabolic acidosis caused by tissue hypoxia is not recommended for pH ≥ 7.10. Bicarbonate therapy is associated with sodium and fluid overload, an increase in lactate and pCO2 and a decrease in serum
ionized calcium. A left shift in the oxy– haemoglobin dissociation curve may aggravate the tissue hypoxia. Hyperchloraemia, caused by the administration of large volumes of 0.9% sodium chloride solution (chloride concentration of 154 mmol/L), may cause metabolic acidosis with normal lactate levels
(12). If serum chloride levels increase, use Hartmann’s solution or Ringer’s lactate as crystalloid. These do not increase the lactic acidosis.
Complications and intensive care management
Many of the complications seen in dengue are preventable if clinical team members are alert to the physiological problems of the three different phases. When hypovolaemic shock is adequately managed, patients appear to “sail out” of the critical phase with mere parenteral fluids. But that belies the effort that has been invested in the monitoring and careful titration of intravenous fluid therapy, guided by frequent clinical and haematocrit evaluation.
Causes of complications in dengue include:
•missed diagnosis at the frontline;
•inadequate monitoring and misinterpretation of vital signs;
•inadequate monitoring of fluid intake and urine output;
•late recognition of shock leading to profound and/or prolonged shock;
•late recognition of severe bleeding;
•too much or too little intravenous fluids i.e. not following/understanding the treatment guidelines;
•careless attitude towards aseptic techniques.
Outcome: These lead to a
•prolonged and/or profound shock;
•severe bleeding with severe disseminated intravascular coagulopathy;
•respiratory distress and failure;
•irreversible shock and death.
This group of patients should be referred to a hospital with intensive care facilities wherever possible. The clinical evaluation of these patients should include: A general inspection of the mental state: remember that shock patients remain quiet but alert until hypotension sets in. An irritable combative dengue patient indicates severe shock with declining cortical perfusion. Confusion, lethargy, seizures and coma will set in very quickly. Other possible causes of change in mental state are fulminant hepatic failure (1, 2), hypoglycaemia, electrolyte abnormalities and rarely, intracranial bleeding and encephalitis (3−5). Airway and breathing: There is usually no problem with the airway. Breathing should be assessed carefully. The patient in early compensated shock has quiet tachypnoea (the lungs are clear). As shock progresses, metabolic acidosis sets in; the breathing then becomes deeper and faster. The lungs remain clear with good air entry. There might be clinically detectable pleural effusion but the question should be: Is this enough to cause the tachypnoea? If no, then this could be Kussmaul’s breathing. Patients with Kussmaul’s breathing will prefer to lie horizontal because of hypovolaemia, whereas patients with true respiratory distress from pulmonary causes will most probably be sitting up for optimal chest wall mechanics.
For pleural effusion to be the cause of the respiratory distress, it should be substantial and easily detectable. The diaphragm may be splinted by tense ascites. This scenario occurs after unrestrained intravenous fluid therapy, not before. Wheezing and rhonchi indicate pulmonary oedema and hypervolaemia, not the presence of asthma. Fine crepitations of pulmonary oedema may not be audible if the breathing effort is poor. Again, this occurs after aggressive or unguided intravenous fluid therapy. Occasionally a combination of metabolic acidosis and fluid overload may be seen in patients who have received inappropriate fluid therapy. Thus they remain in severe shock and have fluid overload at the same time. These patients cannot get comfortable lying down or sitting up and are very restless. The clinical evaluation should be corroborated with radiological findings and blood gas analysis. Diminished air entry in a drowsy patient indicates impending respiratory failure. Cyanosis and gasping respiration is seen in an imminent respiratory arrest.
Circulation: The peripheral perfusion should be assessed by examination and palpation of the extremities and the radial pulse – pulse volume, capillary refill time, temperature, colour of extremities and pulse pressure (see Section 1.1.4). Examine for bleeding (orogastric tube insertion, if indicated), jaundice, evidence of plasma leakage and abdominal tenderness and distension.
Monitoring: Continuous heart rate (ECG), respiration and pulse oximetry should be monitored. With the latter it may be difficult to get a signal in severe shock. Intermittent BP (measured every 5−30 minutes), peripheral perfusion and
Evaluate the history and prior treatment:
•What was the date of onset of fever?
•Which phase of dengue illness is the patient in? Is the patient in the critical phase?
The countdown may begin from the time of defervescence (temperature below 38°C), or apparance of warning signs, or increase in haematocrit, or sudden decrease in platelet count. For those patients who present with shock, the beginning of the critical period could be a few hours before presentation to the hospital. The period of intravenous therapy should therefore be less than 48 hours in those who present to the hospital with shock . Is there evidence of plasma leakage? How many more hours of plasma leakage do you envisage? These timelines may be approximations but will help guide your decision about stopping intravenous fluid therapy.
•Review the fluid intake, output and balance since the start of parenteral fluid therapy. What types of fluids have been administered – hypotonic, glucose solutions, isotonic crystalloids (0.9% sodium chloride solution or Ringer’s lactate or Hartman’s solution), colloids, blood, and blood products? When was the last urine output? What is the amount of urine? Is the urine volume appropriate to the haemodynamic state? How much is the positive fluid balance? A large positive balance of fluid is reflected in large pleural effusions, ascites, respiratory distress and generalized oedema.
•Review the haemodynamic response to the volume and type of intravenous fluid therapy, and the corresponding trends of haematocrit. You will obtain a better understanding of the clinical situation and the dynamics if you view the process in a
• Full blood count, haematocrit, blood glucose, blood gas analysis and lactate should be done for patients with tachypnoea and shock. Serum electrolytes and calcium, liver function tests, blood urea and creatinine
is indicated in all cases of severe dengue shock. Coagulation profile – prothrombin time (PT), partial thromboplastin time (PTT), international normalized ratio (INR), fibrinogen degradation products and fibrinogen level is indicated in severe bleeding.
•Chest radiography – a small heart shadow indicates intravascular depletion. A large heart (cardiothoracic ratio > 0.55) together with prominent pulmonary vascular markings, “bat’s wings” appearance ± Kerley B lines are suggestive of intravascular hypervolaemia and pulmonary oedema. The lung volume may be reduced by the pleural effusion and upward displacement of the diaphragm by gross ascites.
•Determine blood group and match for fresh whole blood or fresh packed cells, at least 10−20 ml/kg aliquot.
•Blood culture and sensitivity (if indicated)
•Dengue diagnostic tests (see Section 1.4)
Key questions to answer:
•Is the patient alert and cooperative or restless, combative or drowsy?
•Is the patient in respiratory distress or failure?
•Does the patient have stable haemodynamics? The arterial, venous or capillary blood gases and lactate levels will complement the clinical information about the hemodynamic stability. As shock progresses, carbon dioxide tension reduces together with a reduced bicarbonate level. A rising lactate level is a sign of worsening tissue perfusion.
•Has the fluid therapy been adequate to maintain the circulation and tissue organ perfusion? Is the patient in the beginning or nearing the end of the critical phase or in the recovery phase?
•Does the patient have intravascular and extravascular fluid overload?
•Is the shock prolonged? Has it been missed? You could track shock by the tachypnoea, tachycardia and/or the period of anuria/oliguria and/or metabolic acidosis.
•Is there hyperglycaemia? If there is, is it related to stress, inappropriate fluids or undiagnosed or uncontrolled diabetes mellitus? Please refer to the information on hyperglycaemia in Section 220.127.116.11.
•Is there electrolyte disturbances? Please refer to section on electrolyte disturbances in Section 18.104.22.168.
•Does the patient have severe overt bleeding? An orogastric tube may reveal fresh bleeding or coffee grounds.
•Does the patient have severe internal/occult bleeding? There are several ways to answer this question. The most direct method: Is the patient’s baseline haematocrit known i.e. the haematocrit on days 1−3 of fever? If yes, then it is valuable information. If not, the population haematocrit may be used, although this will not be as precise as the patient’s own baseline. Many conditions such as iron deficiency,
mild haemolytic disease, chronic smoking, and chronic obstructive sleep apnoea will affect the patient’s baseline haematocrit. o For other ways to answer this very important question, refer to Section 22.214.171.124 on the recognition of severe bleeding. o The earlier this critical condition is recognized, the earlier definitive treatment can be given, saving the patient from receiving several ineffective bolus fluids, most of which will be redistributed to the third spaces.
Prolonged/profound shock is characterized by severe metabolic acidosis ±
If the patient is quietly alert and cooperative, an urgent haematocrit will guide further fluid therapy. If the analysis indicates severe bleeding and matched fresh whole blood (FWB) is available, blood transfusion should be started as soon as possible. However, the following applies if blood is not available:
• If the patient has received < 2 boluses of resuscitation fluid, a colloid solution of 10−20 ml/kg over 15−30 minutes should be used (refer to the algorithm in Figures 5– 7). If the patient has received more than 2 boluses of resuscitation fluid, fluids should be switched to a colloid solution of 10−20 ml/kg over
30 minutes for hypotensive shock, and over 1−2 hours for compensated shock. If severe overt bleeding is apparent (haematemesis, malaena or hypermenorrhoea), the colloid bolus should be followed urgently by transfusion of 10−20 ml/kg FWB, regardless ofthe haematocrit level. After transfusion of FWB, some degree of haemodynamic stability is usually achieved together with improvement of metabolic acidosis. Further colloid infusions may be necessary if the haematocrit rises again. A repeat transfusion of FWB will be required if bleeding continues. Bleeding will usually slow down towards the end of the critical phase.
There is no evidence that transfusion of platelet concentrates or the disseminated intravascular coagulopathy (DIVC) regime is effective. This practice will contribute to third space losses and expose the patient to multiple blood donors. Prolonged stay in the intensive care unit (ICU) is also expected. If no overt bleeding is seen after the colloid bolus, a repeat clinical evaluation and haematocrit level should be performed. A decrease in haematocrit together with clinical improvement means there is
restoration of circulatory volume with colloids. However, a decrease in haematocrit, not accompanied by clinical improvement should prompt the suspicion of severe internal/occult bleeding.
The patient is restless and combative. This patient has prolonged severe shock and is at high risk of dying soon. This scenario is often associated with severe bleeding. In addition to the management as in scenario 1, one should make preparations for tracheal intubation and mechanical ventilation. The patient should be given a high flow oxygen mask, or the airway and breathing should be supported with mask ventilation.
Fresh, safe, group “O” blood should be considered if
If the patient does not respond to the above measures, a concomitant nosocomial infection should be suspected and appropriate antibiotics started.
2.3.1Acute respiratory distress and failure
Causes of acute respiratory distress and failure are:
• severe metabolic acidosis from severe shock
• fluid overload – large pleural effusions and ascites
• acute pulmonary oedema
• acute respiratory distress syndrome (ARDS)
Severe metabolic acidosis from severe shock:
Kussmaul’s breathing will be observed in addition to tachycardia and other signs of shock. Tracheal intubation should not be the first treatment. Instead, these patients should be given treatment as for hypotension shock i.e. prompt resuscitation with fluid boluses after sampling blood for haematocrit determination (refer to algorithm, Figure 7). After fluid resuscitation, evaluate to ensure that the respiratory effort has subsided and that other parameters of adequate circulation are present. Otherwise the haematocrit needs repeating and the question of severe bleeding needs to be considered. A chest radiograph mayindicate that the intravascular volume is depleted but it is the haematocrit that will guide whether transfusion with FWB is required (refer to interpretation of haematocrit and Section 126.96.36.199, Treatment of shock).
Some degree of fluid overload is inevitable in patients with severe plasma leakage. The skill is in giving them just enough intravenous fluid to maintain adequate perfusion to keep them alive, while waiting it out until the plasma leakage process spontaneously reverses, and at the same time avoiding excessive fluid overload.
Causes of excessive fluid overload are:
•excessive and/or too rapid intravenous fluids during the critical phase;
•incorrect use of hypotonic crystalloid solutions e.g. 0.45% sodium chloride solutions;
•inappropriate use of large volumes of intravenous fluids in patients with unrecognized severe bleeding;
•inappropriate transfusion of
•prolonged intravenous fluid therapy, i.e., continuation of intravenous fluids after plasma leakage has resolved (> 48 hours from the start of plasma leakage);
Early clinical features of fluid overload are:
•respiratory distress, difficulty in breathing;
•large pleural effusions;
•tense ascites, persistent abdominal discomfort/pain/tenderness (this should not be interpreted as warning signs of shock);
•increased jugular venous pressure (JVP).
Late clinical features are:
•pulmonary oedema (cough with pink or frothy sputum, wheezing and crepitations, cyanosis) - this may be mistaken as pulmonary haemorrhage;
•irreversible shock (heart failure, often in combination with ongoing hypovolaemia).
Additional investigations are:
•blood gas and lactate analysis; the chest
•ECG to exclude ischaemic changes and arrhythmia;
•echocardiogram for assessment of left ventricular function and left ventricular enddiastolic diameters (LVEDD) and regional wall dyskinesia that may suggest underlying ischaemic heart disease. The LVEDD is a reliable measure of the filling volume of the left ventricle and is increased in hypervolaemia. Other indirect measures of the intravascular compartment status are the sizes of internal jugular
vein and inferior vena cava;
•cardiac enzymes. Action plan:
•Oxygen therapy should be given immediately.
•The further action plan for the treatment of fluid overload is dependent on the patient’s haemodynamic stability, intravascular volume status and the timing of this event with respect to the timeline of the critical phase.
Strong pulses with warm extremities are positive indications to stop (if ≥ 48 hours of plasma leakage) or reduce (if ≤ 48 hours of plasma leakage) intravenous fluids. The haematocrit is typically low; however it may remain elevated in some patients. The
support may be indicated depending on the severity of respiratory distress. Recognizing when to decrease or stop intravenous fluids is crucial to preventing fluid overload (see Section 188.8.131.52).
The patient has stable haemodynamic status but is still within the critical phase, < 48 hours of plasma leakage. The
Patients who remain in shock with elevated haematocrit levels but show excessive fluid accumulation are likely to have received rapid infusions of crystalloid or hypotonic solutions or blood products. In these patients a carefully titrated bolus of colloid solution at 5−10 ml/kg/hour for
Patients who remain in shock with low or normal haematocrit levels but have excessive fluid accumulation, are most likely to have severe occult bleeding (see Section 184.108.40.206). If the BP is low, a dopamine infusion should be started. Further infusion of large volumes of intravenous fluids will lead to a poor outcome. Careful transfusion of FWB, at least 10 ml/kg, should be initiated as soon as possible at a rate titrated to a clinical response, blood gases and lactate. Respiratory support may be required; refer to section on mechanical ventilation.
A combination of scenarios 3 and 4 may play out in some cases. Patients with both intravascular and extravascular fluid overload remain in shock with metabolic acidosis because the severe bleeding has been replaced with
Pulmonary oedema and acute respiratory distress syndrome (ARDS)
These two conditions will cause
The goals of therapy are to optimize oxygenation and ventilation with respiratory support and stabilize the haemodynamic situation.
•Apart from increasing the fractional inspired oxygen, positive
•Patients who are alert, cooperative and haemodynamically stable with no, or mild, metabolic acidosis may benefit from
•If the patient is out of the plasma leakage phase and has stable haemodynamics, intravenous fluid therapy should be discontinued and diuretic therapy can be commenced cautiously. Please refer to Section 2.3.2.
• Indications for mechanical ventilation include:
o patients who have shock and are restless, combative or confused; o respiratory failure from acute pulmonary oedema/ARDS ± shock; o patients who fail to respond to
Undertaking a tracheal intubation in a dengue shock patient is a risky procedure for the following reasons:
•Sedation and induction agents will precipitate hypotension and cardiac arrest in a hypovolaemic patient. Unless the tidal volume and respiratory rate (RR) are increased to match those of the patient’s own respiratory effort, muscle relaxants will worsen the metabolic acidosis by removing the respiratory compensation. This will further precipitate hypotension and cardiac arrest.
•The compliance of the respiratory system will be diminished by the pleural effusion and ascites, so higher pressures will be required to achieve adequate ventilation and oxygenation.
•Trauma to the airway will cause bleeding which will block the tracheal tube.
2.3.4 Haemophagocytic syndrome
Evidence of haemophagocytosis in dengue was alluded to by the presence of numerous macrophages that have phagocytosed erythrocytes and lymphocyte phagocytosis in the spleen (7, 8). The unusual incidence of phagocytic reticulum cells which phagocytosed all blood elements has been reported (9−11). The clinical significance of reactive haemophagocytosis in dengue has not been studied. However, case reports of prolonged fever in dengue patients have been attributed to this phenomenon. The clinical picture is characterized by persistent high fever, variable cytopenia and
2.3.5 Supportive care and adjuvant therapy
Supportive care and adjuvant therapy may be necessary in severe dengue and includes:
Vasopressor and inotropic therapy
The use of vasopressor and inotropic therapy should be limited to the following clinical situations:
•As a temporary measure to prevent
•Evidence of cardiogenic shock due to myocarditis or ischemic heart disease. Dobutamine is the recommended choice. In concomitant septic shock, dopamine or norepinephrine are the vasopressors of choice. Vasopressor therapy should be carefully monitored since dengue shock is primarily a
hypovolaemic shock caused by plasma leakage ± haemorrhage. The most essential and effective strategy is the correction of intravascular volume with the appropriate types of
2.3.4 Haemophagocytic syndrome
Evidence of haemophagocytosis in dengue was alluded to by the presence of numerous macrophages that have phagocytosed erythrocytes and lymphocyte phagocytosis in the spleen (7, 8). The unusual incidence of phagocytic reticulum cells which phagocytosed all blood elements has been reported (9−11).
The clinical significance of reactive haemophagocytosis in dengue has not been studied. However, case reports of prolonged fever in dengue patients have been attributed to this phenomenon. The clinical picture is characterized by persistent high fever, variable cytopenia and
Definitive diagnosis is made by bone marrow biopsy which demonstrates haemophagocytic activity. Response to
2.3.5 Supportive care and adjuvant therapy
Supportive care and adjuvant therapy may be necessary in severe dengue and includes:
Vasopressor and inotropic therapy
The use of vasopressor and inotropic therapy should be limited to the following clinical situations:
•As a temporary measure to prevent
•Evidence of cardiogenic shock due to myocarditis or ischemic heart disease. Dobutamine is the recommended choice. In concomitant septic shock, dopamine or norepinephrine are the vasopressors of choice. Vasopressor therapy should be carefully monitored since dengue shock is primarily a hypovolaemic shock caused by plasma leakage ± haemorrhage. The most essential and effective strategy is the correction of intravascular volume with the appropriate types of
2.4.7 Dengue in paediatric cases
Dengue virus infections affect human populations of all age groups worldwide. In some parts of the world, dengue is mainly a paediatric health problem. The vast majority of dengue cases occur in children < 15 years of age and around 5% of all severe dengue cases occur in infants
infants acquire primary dengue virus infections (1,
Manifestations of dengue in infants
As in older children and adults, dengue virus can cause a spectrum of outcomes in infants, ranging from asymptomatic infection to mild or clinically significant, severe disease (5). The burden of severe dengue lies predominantly in infants
Hepatomegaly is usually noted (2, 6, 7, 8). Splenomegaly is seen in almost 10% of dengue infants, seven times more frequently than in older children (2, 6, 8). Shock occurs when a critical volume of plasma is lost through leakage. As with older children, it is often preceded by warning signs. The body temperature may be subnormal when shock occurs. However, some infants may still have fever at the onset of shock; in these patients a differential diagnosis of septic shock should be kept in mind (6). With prolonged shock, the consequent organ hypoperfusion results in multiple organ dysfunction, metabolic acidosis and disseminated intravascular coagulation. The degree of increase above the baseline haematocrit often reflects the severity of plasma leakage. Haemoconcentration, manifested by an increase in haematocrit of ≥ 20% above the baseline haematocrit may be seen (6, 9). The normal value of haematocrit in infants 2– 12 months of age is relatively low
Management of dengue in infants
Severe dengue is less common in infancy but when it does occur the risk of dying is higher than in older children and adults (3, 6, 11). Infants with dengue should be referred for inhospital management.
Management of dengue infants without warning signs
Treatment is supportive. Oral rehydration should be encouraged with oral rehydration solution (ORS), fruit juice and other fluids containing electrolytes and sugar, together with breastfeeding or formula feeding and/or solid food. Febrile seizures are more frequent in infants and young children with dengue than in older patients. Parents or caregivers should be instructed about fever control with antipyretics and tepid sponging. Advise the parent or caregiver to bring the infant back to the nearest hospital immediately if the infant has any of the warning signs.
Fluids account for a greater proportion of body weight in infants than children and minimum daily requirements are correspondingly higher. Infants have less intracellular fluid reserve than older children and adults. Moreover, capillary beds are intrinsically more permeable than those of older children or adults. Both early cardiovascular compromise and significant fluid overload are more likely if capillary leaks occur in these circumstances (12).
Intravenous fluid therapy is indicated when the infant has dengue with warning signs. Judicious volume replacement of lost plasma by intravenous fluid therapy from this early stage may modify the course and severity of the disease. Only isotonic crystalloid solutions such as Ringer's lactate (RL), Ringer's acetate (RA), or 0.9% saline solution should be used. Start with
Management of infants with severe dengue
Treatment of shock (see Section 220.127.116.11 for more details) Volume replacement in infants with dengue shock is a challenging management problem. The strategy for fluid resuscitation in infants is similar to that in children and adults. The recommended regimen for the treatment of infants with dengue shock is as follows:
•Immediate and rapid replacement of the plasma loss with isotonic crystalloid solutions or, in the case of profound shock, colloid solutions.
•Continued replacement of further plasma losses to maintain effective circulation for
•Correction of metabolic and electrolyte disturbances.
•Blood transfusion – only to cases with severe bleeding. Treatment of compensated shock in infants:
Please refer to Section 18.104.22.168 Treatment of profound shock (hypotensive; undetectable pulse and BP) in infants: Please refer to Section 22.214.171.124 Clinicians who take care of
In patients with profound, recurrent or prolonged shock, a central venous catheter may be inserted through the antecubital basilic vein or internal jugular vein to guide intravenous fluid therapy. This should be done by an experienced member of staff using ultrasound to guide the insertion (if available).
In infants intravenos only indicated in dengue infants with severe bleeding (see Section 126.96.36.199). Hyponatraemia and metabolic acidosis can occur in severe cases. Electrolyte levels and blood gases should be determined periodically in severe cases. Early volume replacement will usually correct the metabolic acidosis and generally result in a favourable outcome. Sodium bicarbonate may be considered in severe metabolic acidosis.
Although dengue in infants comprises around 5% of all paediatric cases, mortality rates are higher in infants than in older children (3, 6, 13). Fluid replacement in infants with severe dengue is a challenge to
good clinical management. This involves following established procedures for use of colloid solutions and blood transfusions. To further reduce case fatalities, special emphasis needs to be given to dengue infants who have severe complications or who go on to develop them.
Vertical transmission and neonatal dengue
Pregnant women with dengue virus infection can transmit the virus to their foetus and vertical dengue transmission has been described. Questions about dengue in pregnant women relate to the effect of the pregnancy on the disease process; the effect of the disease on the pregnancy; possible effects on the foetus and the neonate; and how the pregnant woman and the newborn might best be managed (14). Answers to questions about the effect of the disease on the pregnancy are discussed in Section 2.4.5 of thishandbook. Here follows a review of the effects of dengue on the neonate, clinical manifestations and management of neonatal dengue. Dengue virus can be vertically transmitted to the foetus in utero or to the infant at parturition. Results of a recent systematic review indicate 16 cases of vertical transmission among 25 (64.0%) neonates reported from 12 case reports, and vertical transmission occurring in 4 of the 10 case series, in 18 of 143 (12.6%) of cases (15). One comparative study that tested 64 umbilical cord serum samples for dengue IgM from 63 women who were found to be IgM positive at the time of delivery, found a vertical transmission rate of 1.6% (16).
In the vertical transmission cases, some newborns may be asymptomatic (16). Clinical manifestations of vertically infected neonates vary from mild illness such as fever with petechial rash, thrombocytopenia and hepatomegaly, to severe illness with clinical sepsis, pleural effusion, gastric bleeding, circulatory failure, massive intracerebral haemorrhage and death (17−24). Clinical presentation in the newborn infant does not appear to be associated with maternal disease severity or dengue immune status, or mode of delivery (19, 24, 25). However, timing of maternal infection may be important; peripartum maternal infection may increase the likelihood of symptomatic disease in the newborn. A review of 17 mother– infant pairs with dengue infection found that the time intervals between the mothers’ onset of fever and that of their neonates, were
Management of neonatal dengue
When a pregnant or parturient woman develops signs consistent with dengue, the diagnosis of dengue should be considered in her neonate even if the neonate appears well in the first several days of life. Remember that some neonates have become ill as long as 11 days after birth (24). The diagnosis of neonatal dengue could eventually be suspected on clinical grounds and then confirmed in the laboratory, but initial presentation may be confused with bacterial sepsis, birth trauma and other causes of neonatal illness. Symptomatic and supportive treatment under close observation is the mainstay of treatment (14, 20, and 24).
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