Acute interventions (Table ) refer to treatments recommended to be administered without delay. Although acute interventions are presented and suggested in this manuscript in a certain order (Fig. ), some interventions could and should be performed simultaneously, depending on the condition of the patient.
- Use adequate tissue perfusion as the principal endpoint of resuscitation (LoE: A). In addition, target a systolic arterial blood pressure >90 mmHg in adults, as well as normal heart rate and arterial blood pressure in children (LoE: D).
Given that tissue hypoperfusion is a key factor contributing to sepsis-associated organ failure [17
], one principal goal of resuscitation is to promptly restore tissue perfusion [6
]. Although adequate tissue perfusion is often associated with a systolic arterial blood pressure >90 mmHg, some patients may restore tissue perfusion with lower arterial pressures. On the other hand, achievement of a normal arterial blood pressure is not necessarily associated with adequate tissue perfusion [18
]. Therefore, arterial blood pressure alone is not a reliable endpoint for assessing adequacy of tissue perfusion. Although no clinical parameter exists to directly assess adequacy of tissue perfusion, clinical variables presented in Table may be used [19
]. Clinical signs of dehydration (e.g., dry mucous membranes, skin tenting) are rare in acute sepsis and should make the clinician consider a sub-acute or chronic disease process with superimposed infection.
- In patients with tissue hypoperfusion, infuse fluids aggressively and continue liberal infusions for 24–48 h (LoE: C). More than 4 L during the first 24 h may be required to adequately resuscitate the adult septic patient.
Clinical indicators of adequate tissue hypoperfusion
Despite the development of interstitial edema, hypovolemia arising from true fluid loss or capillary leakage with interstitial edema formation is a main cause of tissue hypoperfusion in sepsis [20
]. Fluid therapy increases systemic blood flow and oxygen delivery [21
]. Aggressive fluid resuscitation reduced mortality in patients with typhoid ileal perforation in rural Africa [22
]. In Ugandan patients with Gram negative bacteremia, mortality was decreased in patients receiving >1 L of fluid compared to those receiving less or no fluids [23
]. Children with septic shock receiving <20 mL/kg of fluids had twice as high mortality compared to children receiving >40 mL/kg of fluids during the first hour [24
]. Fluid resuscitation is of particular importance in children with the Dengue shock syndrome, a clinical scenario characterized by vascular leakage and hypovolemia [25
A recent study by Maitland et al. [27
] reported increased mortality in African children (median age 24 months) with sepsis who received fluid boluses in addition to maintenance fluids (2.5–4 mL/kg/h). Harmful effects of fluid boluses were mainly observed in children with compensated shock and profound anemia. More than half of the children had malaria, a state where microcirculatory dysfunction is common due to sequestration of parasitized erythrocytes rather than frank hypovolemia. Widespread lack of intensive care facilities among study centers may have contributed to harmful effects of aggressive fluid loading.
Based on these data, patients with sepsis and tissue hypoperfusion appear to benefit from a rapid bolus of intravenous crystalloid solution of at least 20 mL/kg. Further fluid resuscitation should be guided by the response to fluid loading. A positive response to fluid loading can be considered as one of the following: >10% increase of systolic/mean arterial blood pressure, >10% reduction of heart rate, and/or improvement of mental state, peripheral perfusion and/or urine output. Some adult patients may require several liters of fluids during the first 24–48 h to achieve this goal. Likewise, fluid amounts as high as 110 mL/kg may be required in children with septic shock during early resuscitation [28
]. In children with profound anemia and severe sepsis, particularly due to malaria, fluid boluses must only be administered cautiously, and blood transfusion should be considered instead [27
Fluid resuscitation should be stopped or interrupted when no improvement of tissue perfusion occurs in response to volume loading. Development of crepitations in adults plus hepatomegaly in children indicate fluid overload or impaired cardiac function. Since aggressive fluid resuscitation can lead to respiratory impairment, additional fluid resuscitation following the initial fluid boluses should be performed carefully if no mechanical ventilator is available. In such a scenario, it may be necessary to balance adequate pulmonary gas exchange against optimum intravascular filling. However, this is an infrequent conundrum within the first 6 h.
Fluid administration in septic patients should occur intravenously even if access needs to be attained by surgical cut-down or central venous cannulation. Alternatively, an intra-osseous access may be used. An intra-osseous cannula should only be used if running freely and for <24 h. Although oral rehydration is efficient to treat dehydration [29
], no data on the efficacy and safety of oral rehydration in septic patients with tissue hypoperfusion exist. Considering a relevant aspiration risk, oral rehydration should be avoided in septic shock patients.
- Use crystalloids and/or colloids for fluid resuscitation (LoE: B). When available, use colloid solutions in children with severe Dengue shock syndrome (LoE: B).
There are no data supporting the superiority of colloid over crystalloid solutions for resuscitation of adults or children with bacterial sepsis [28
]. In most situations, adequacy of fluid resuscitation is more relevant than the type of fluid infused. Considering high costs [32
], the risk of allergies [33
] and potential renal and coagulatory side effects [34
] of colloids, crystalloid solutions appear more suitable in resource-limited settings. However, colloids may bear potential benefits in children with severe Dengue shock syndrome (pulse pressure ≤10 mmHg) [25
]. In moderate Dengue shock syndrome (pulse pressure >10 and ≤20 mmHg) colloid and crystalloid solutions lead to similar outcomes. Since moderate Dengue shock syndrome is more common than severe, crystalloids remain the first-line fluid in the majority of cases [25
- Use dopamine or epinephrine (adrenaline) in patients with persistent tissue hypoperfusion despite liberal fluid resuscitation (LoE: C).
Background If fluid resuscitation cannot restore tissue perfusion, the use of dopamine or epinephrine (adrenaline) should be considered. While cool extremities, extended neck veins, crepitations or crackles, a third or fourth heart sound, and/or a positive hepato-jugular reflux characterize the patient with impaired heart function, patients with excessive peripheral vasodilation typically present with warm extremities, oliguria and impaired mental state. In many cases, however, it is difficult to differentiate between the two states without measuring cardiac output. Arrhythmogenic and obstructive causes of fluid-resistant tissue hypoperfusion (e.g., pneumothorax, pericardial tamponade, abdominal compartment syndrome) must be excluded.
Studies suggest that neither dopamine nor epinephrine is inferior to a balanced infusion of norepinephrine (noradrenaline) and dobutamine with respect to septic shock outcome [35
]. Considering frequent aggravation of lactic acidosis during epinephrine infusion [38
], norepinephrine should, whenever available, be preferred over epinephrine. Since all catecholamines typically exert dose-dependent adverse side effects, doses should be kept at a minimum. Although dopamine-refractory shock may be reversed with epinephrine or norepinephrine infusion in children [39
], combined use of dopamine and epinephrine is discouraged.
Preferentially, dopamine or epinephrine is infused through a central venous catheter. If central venous catheters are unavailable or the medical staff has insufficient experience handling them [40
], a peripheral venous cannula, placed in a large bore vein, or an intra-osseous cannula can be used. It is important to frequently check the site of infusion for signs of drug extravasation, since substantial skin necrosis may occur [41
]. Dopamine and epinephrine should be administered continuously. When pumps are unavailable or power cuts frequently occur, dopamine (e.g., 250 mg) or epinephrine (e.g., 5–10 mg) can be diluted in 500 mL of crystalloid solution and infused using a drop regulator or micro-infusion set. Dosing should occur based on the clinical response.
- In patients requiring dopamine or epinephrine (adrenaline) measure arterial blood pressure and heart rate frequently (LoE: D).
In children and adults requiring dopamine or epinephrine (adrenaline), blood pressure should be measured frequently [6
]. The invasive technique is rarely available in resource-limited settings and requires specific training. Alternatively, blood pressure can be measured non-invasively. Specifically in children, adequately sized cuffs must be used to ensure accurate readings. Intervals for non-invasive blood pressure measurements should be set at 5–15 min as long as epinephrine or dopamine is infused.
- Administer intravenous hydrocortisone (up to 300 mg/day) or prednisolone (up to 75 mg/day) to adult patients requiring escalating dosages of epinephrine (adrenaline) or dopamine (LoE: B). Consider the use of equivalent hydrocortisone or prednisolone doses in children with severe shock (LoE: C).
Relative adrenal insufficiency with inadequately low plasma cortisol levels is frequent in septic shock [42
]. If hydrocortisone is administered to adults requiring escalating catecholamine doses in high-income settings, shock duration and mortality are reduced [42
]. An Indian randomized pilot study suggested a trend towards earlier shock reversal and less inotrope use when hydrocortisone (5 mg/kg/day in four divided doses followed by half the dose for a total of 7 days) was administered to children with septic shock [44
]. Until more data are available, use of hydrocortisone must be considered a rescue therapy in pediatric septic shock. Daily corticosteroid dosages must not exceed equivalent doses of 300 mg hydrocortisone or 75 mg prednisolone, since higher doses may predispose for infections [45
]. Corticosteroids should not be administered to patients not requiring catecholamines unless they are on chronic corticosteroid therapy. When epinephrine or dopamine can be withdrawn, corticosteroids should be tapered off (over days) to avoid rebound hypotension [42
- Apply oxygen to achieve an oxygen saturation >90% (LoE: B). If no pulse oximeter is available administer oxygen empirically in patients with severe sepsis or septic shock (LoE: D).
Apart from tissue hypoperfusion, organ dysfunction associated with sepsis arises from hypoxemia [46
], which is highly prevalent in resource-limited settings [47
]. Clinical signs (e.g., cyanosis) are not reliable, particularly in patients with dark complexion. Clinical signs of respiratory distress (dyspnea, increased work of breathing) reflect changes in respiratory mechanics and may not be reliable gauges of hypoxemia. Therefore, it is essential to monitor septic patients with a pulse oximeter [48
]. Patients presenting with hypoxemia should receive oxygen to achieve an oxygen saturation >90%. In Papua New Guinea, installation of hospital wide oxygen systems facilitated oxygen therapy for hypoxemic children with pneumonia and reduced the risk of death [50
]. If no pulse oximeter is available, oxygen should empirically be administered to all septic patients (see Electronic Supplementary Material for technical details).
- Place patients in a semi-recumbent position (head of the bed raised to 30–45°) (LoE: C).
Unless hemodynamically unstable, septic patients should be placed in a semi-recumbent position (head of the bed raised to 30–45°). Semi-recumbency reduces the risk of tracheal aspiration and hospital-acquired pneumonia, particularly when mental state is impaired or enteral nutrition administered [51
- Unconscious patients should be placed in the lateral position. The patient’s airway should be kept clear (LoE: C).
Unconscious patients and subjects who cannot keep their airway open for other reasons should be placed in the lateral position. In addition, an oro- or nasopharyngeal airway can be inserted if the lateral position alone cannot maintain airway patency. Inability to clear the airway is associated with a high risk for aspiration of saliva or regurgitated gastric contents. Oral hygiene (tooth brushing and cleansing with an oral antiseptic at least twice daily), repetitive suctioning of oropharyngeal secretions and placement in the semi-recumbent position (also the lateral position) can prevent pneumonia [53
- If available and medical staff is adequately trained, use non-invasive ventilation in patients with dyspnea and/or persistent hypoxemia despite oxygen therapy (LoE: C).
Sepsis may lead to deterioration of lung function. In severe cases, respiratory insufficiency may not be sufficiently treated by oxygen alone, even when administered at high flow rates. Wherever available and when medical staff is adequately trained, mechanical ventilation should be instituted early in patients with increased work of breathing and/or persistent hypoxemia despite oxygen therapy. In many resource-limited settings, non-invasive mechanical ventilation (administration of ventilatory support through a mask instead of an endotracheal tube or tracheostoma) appears to be the ventilation technique of choice [54
]. Non-invasive ventilation has been applied with good success in patients with acute respiratory failure in Pakistan [55
]. Data from India reported that non-invasive intermittent positive pressure ventilation decreased the need for endotracheal intubation in acute respiratory failure of diverse origin [56
]. Nasal continuous positive airway pressure improved the management of respiratory insufficient children with Dengue hemorrhagic fever in Southeast Asia [57
]. Despite these positive reports, studies performed in high-income settings demonstrate that not all patients can successfully be managed with non-invasive ventilation [54
]. This is specifically true for septic patients with impaired consciousness, severe respiratory or cardiovascular failure. Particularly young children may not tolerate non-invasive ventilation. Furthermore, airway anatomy (large tongue, short neck) combined with the need for lower tidal volumes makes non-invasive ventilation in children difficult [58
If equipment is available and medical staff adequately trained, mechanical ventilation may be delivered via an endotracheal tube. When doing so an adequate level of positive end-expiratory pressure with tidal volumes of 6 mL/kg ideal body weight should be set [59
Furthermore, peak (pressure control ventilation mode) or plateau (volume control ventilation mode) pressures should not exceed 30 cmH2
]. Spontaneous breathing modes are equally preferred in intubated patients [62
]. If mechanical ventilators are unavailable, anesthetic circuits or machines may be used to ventilate a patient with respiratory distress or during the postoperative period.
- Initiate sepsis treatment as early as possible (LoE: B). Antimicrobials should be given within 1 h of recognizing sepsis (LoE: C).
Robust evidence indicates that timely diagnosis of sepsis and rapid initiation of treatment reduces morbidity and mortality both in children and adults [63
]. In a high-income country, each hour of delay in antibiotic administration was associated with an average 7.6% decrease in survival of septic shock [66
]. Similarly, in a predominantly HIV-infected septic patient population in Uganda, any delay in the administration of adequate antibiotics increased all cause and attributable mortality [23
]. Likewise, pre-referral administration of rectal artesunate reduced death in severe malaria in rural Asia and Africa [69
- Administer intravenous antimicrobials at adequate dosages and with a high likelihood to be active against the suspected bacterial pathogens (LoE: C).
Intravenous antimicrobial therapy is one of the key treatments in septic patients. If intravenous access cannot be promptly attained in children, first antimicrobial dosages may be administered intra-muscularly or by the oral or rectal route. Two factors critically determine the benefit of antimicrobial therapy both in resource-rich [66
] and resource-limited settings [22
]: timing and adequacy. Since the causative pathogen cannot be identified immediately, antimicrobial therapy must be started empirically. To ensure that empirical antimicrobial therapy is active against the causative microorganisms, it is vital to account for the likely pathogen spectrum. In middle- and low-income settings, this is particularly challenging since the range of infectious diseases and causative microorganisms is broad, including bacterial, viral, fungal and parasitic pathogens [23
]. Further difficulties arise from frequent antimicrobial resistance [70
], common preceeding self-medication with over-the-counter antibiotics [71
] and the limited availability of potent intravenous antimicrobials [12
]. Considerable regional heterogeneities in these aspects make recommendation of empirical antimicrobial strategies difficult. In a multicenter study performed in middle- and low-income countries, chloramphenicol was superior to injectable ampicillin plus gentamicin in the treatment of community-acquired severe pneumonia in children aged 2-59 months [73
]. To optimize chances of appropriate empirical antimicrobial therapy, empiric antimicrobial therapy should be adjusted to local infectious disease patterns including HIV/AIDS prevalence, pathogen spectrum and antimicrobial resistance.
Adequate dosing is another important aspect of antimicrobial therapy. Considering the high risk of death associated with sepsis, antimicrobial drugs need to be administered at maximum recommended dosages during the initial phase [74
]. This is of particular importance if antimicrobials of unclear quality (e.g., counterfeit or expired drugs) are used. Following the acute phase, many antibiotics require dose adjustments to renal or hepatic function. To achieve optimum bioavailability, the intravenous route is preferred. When the patient improves, antimicrobials may be administered orally provided that intestinal absorption is maintained.
- Perform a detailed patient history and thorough clinical examination to identify the source of infection (LoE: D). Use imaging techniques when available (LoE: D).
Following first resuscitation steps and initiation of empirical antimicrobial therapy, it is critical to identify the source of infection. A thorough patient history and clinical investigation are essential to do so. Although imaging techniques (e.g., X-ray, ultrasound) may be used to answer specific diagnostic questions, nothing can replace a thorough medical history and systematic head-to-toe examination.
- Whenever possible and without harm to the patient, sample fluid or tissue from the site of infection (LoE: C).
Microbiological identification of the causative microorganism of sepsis is useful to confirm presence the diagnosis and allows for targeted antimicrobial therapy. For microbiological cultures, blood, fluid or tissue from the suspected site of infection needs to be sampled in a sterile fashion [75
]. Whenever clinically justifiable and timely achievable this should be done before initiation of empirical antimicrobial therapy to maximize the sensitivity of microbiological cultures. If microbiological cultures are unavailable, it may still be rational to collect samples for visual or microscopic analysis.
- Examine the sampled fluid or tissue by Gram stain, culture and whenever possible for antibiotic susceptibility (LoE: C).
Background After samples have been obtained, transport to the microbiological laboratory should take place as fast as possible. Gram staining and microscopic examination should be performed whenever applicable. Also in resource-limited areas, microbiological cultures remain the gold standard to cultivate microbes. When microorganisms grow, susceptibility to locally available antibiotics should be assessed allowing for targeted antimicrobial therapy. Where parasitic infections are endemic or suspected specific laboratory tests should be used (e.g., thick smear analysis for diagnosis of malaria). Rapid communication of positive microbiological test results to the clinician in charge is imperative.
- Whenever possible drain or debride the source of infection (LoE: C).
Along with timely and adequate antimicrobial therapy, source control is the only causative therapy of sepsis. As soon as basic resuscitation measures and empiric anti-infective therapy have been instituted, source control measures must be prioritized. Source control measures should be timed depending on several factors such as the patient’s condition, surgical expertise and resource availability. In invasive Staphylococcus aureus
infection, source control reduced mortality in a provincial hospital in northeast Thailand [76
]. Typical infectious sources requiring emergent source control measures are abscesses (except for pulmonary abscesses), necrotizing soft tissue and wound infections, gastrointestinal perforation, cholangitis, obstructive urinary tract infection, and any deep space infection such as pleural empyema or septic arthritis. Depending on local availability of experts and resources, the least invasive technique should be chosen (e.g., percutaneous/endoscopic instead of surgical abscess drainage). Not all infectious sources are amenable to surgical source control (e.g., pneumonia, meningitis). In these patients, timing and adequacy of antimicrobial therapy remain the key component of sepsis care.
- Remove any foreign body or device that may potentially be the source of infection (LoE: C).
Device-related infections are particularly frequent in intensive care units of middle- and low-income countries [77
]. Any artificial device (e.g., venous catheter) should carefully be checked for signs of infection. When signs of infection are present, removal of the device represents the key treatment. Infectious signs are frequently insensitive to diagnose infections arising from artificial devices, since infection of internal parts of the device may not cause cutaneous reactions. Therefore, removal of artificial devices should be considered if device-related infection is suspected. Before explanting permanent intravascular (e.g., implanted central venous access) or surgically introduced devices (e.g., hip or knee prosthesis, cardiac pacemaker), other sources of infection need to be safely excluded.