Fundamental Treatment Strategies in Sepsis
(Level I) Begin as soon as recognized and not delayed pending ICU admission. Elevated lactate may identify tissue hypoperfusion in at-risk normotensive patients, however there is some dispute as to its precision as a tissue metabolic status monitor. During the first 6 hrs, the goals of initial resuscitation should be:
- Central venous pressure: 8–12 mm Hg (12 – 15 mm Hg on the vent)
- Mean arterial pressure >= 65 mm Hg
- Urine output >= 0.5 mL•kg-1•hr-1
- SVC or mixed venous O2 saturation = 70%
In mechanically ventilated patients, target a higher central venous pressure (12–15 mm Hg, b/c of increased intrathoracic pressure). Similar consideration may be warranted in circumstances of increased abdominal pressure. A decrease in elevated pulse with fluid resuscitation is often a useful marker of improving intravascular filling [NEJM 345: 1368, 2001] (Level I).
During the first 6 hrs of resuscitation of severe sepsis or septic shock, if central venous O2 saturation or mixed venous O2 saturation of 70% is not achieved with fluid resuscitation to a central venous pressure of 8–12 mm Hg, transfuse PRBC to achieve a hematocrit of > 30% and/or administer a dobutamine infusion (up to a maximum of 20 µg•kg-1•min-1) to achieve this goal [NEJM 345: 1368, 2001]
(Level IV or V) IV antibiotic therapy should be started within one hour of diagnosis but only after appropriate cultures have been obtained. This may require additional vascular access ports (fluid resuscitation should already be in place). (Level III) Although restricting the use of broad-spectrum antibiotics is important for limiting superinfection and resistance, patients with severe sepsis or septic shock warrant broad-spectrum therapy until the causative organism and its antibiotic susceptibilities are defined, at which point restriction of the number of antibiotics and narrowing the spectrum of antimicrobial therapy is an important and responsible strategy.
(Level IV or V) The antimicrobial regimen should always be reassessed after 48–72 hrs. Once a causative pathogen is identified, there is no evidence that combination therapy is more effective than monotherapy. The duration of therapy should typically be 7–10 days and guided by clinical response. Some experts prefer combination therapy for patients with Pseudomonas. Most experts would use combination or broad-spectrum therapy for neutropenic patients. Use of antimicrobial agents with a more narrow spectrum and reducing the duration of therapy will reduce the likelihood that the patient will develop superinfection with pathogenic or resistant organisms such as Candida, Clostridium diff., or VRE.
(Level II) There is no evidence-based support for colloids or crystalloids over one another. Prospective studies of choice of fluid resuscitation in patients with septic shock only are lacking, but meta-analyses indicate no clinical outcome difference (Level IV or V).
Fluid challenge in patients with suspected hypovolemia may be given at a rate of 500–1000 mL of crystalloids or 300–500 mL of colloids over 30 mins and repeated based on response (increase in BP and UOP) and tolerance (evidence of intravascular volume overload, ex. pulmonary edema). Input is typically much greater than output, and input/output ratio is of no utility to judge fluid resuscitation needs during this time period.
(Level IV or V) When an appropriate fluid challenge fails to restore adequate blood pressure and organ perfusion, therapy with vasopressor agents should be started. Vasopressor therapy may also be required in the face of life-threatening hypotension, even when hypovolemia has not yet been corrected. It is important to supplement goals such as blood pressure with assessment of global perfusion such as blood lactate concentrations.
(Level III) Norepinephrine or dopamine through a central catheter as soon as available is the first-choice vasopressor in septic shock (there is no high quality primary evidence to recommend one over another, but epinephrine may cause tachycardia and splanchnic circulation reductions, while phenylephrine may decrease stroke volume. Dopamine increases mean arterial pressure and cardiac output, primarily due to an increase in stroke volume and heart rate. Norepinephrine increases mean arterial pressure due to its vasoconstrictive effects, with little change in heart rate and less increase in stroke volume compared with dopamine. Norepinephrine is more potent than dopamine and may be more effective at reversing hypotension in patients with septic shock. Dopamine may be particularly useful in patients with compromised systolic function but causes more tachycardia and may be more arrhythmogenic (Level I) Low-dose dopamine should not be used for renal protection as part of the treatment of severe sepsis (Lancet 356: 2139, 2000).
(Level IV or V) Patients requiring vasopressors should have an arterial catheter placed as soon as practical. In shock states, measurement of blood pressure using a cuff is commonly inaccurate.
(Level IV or V) Vasopressin use may be considered in patients with refractory shock despite adequate fluid resuscitation and high-dose conventional vasopressors, not as a replacement for norepinephrine or dopamine. If used in adults, it should be administered at infusion rates of 0.01– 0.04 units/min. It may decrease stroke volume (no outcome data are available). Vasopressin is a direct vasoconstrictor without inotropic or chronotropic effects and may result in decreased cardiac output and hepatosplanchnic flow. Most reports exclude patients from vasopressin if the cardiac index is < 2 or 2.5 L•min-1•m-2, and it should be used with caution in patients with cardiac dysfunction. Doses > 0.04 units/min have been associated with myocardial ischemia, significant decreases in cardiac output, and cardiac arrest.
(Level IV or V) In patients with low cardiac output despite adequate fluid resuscitation, dobutamine may be used to increase cardiac output. If used in the presence of low blood pressure, it should be combined with vasopressors. Dobutamine is the first-choice inotrope for patients with measured or suspected low cardiac output in the presence of adequate left ventricular filling pressure (or clinical assessment of adequate fluid resuscitation) and adequate mean arterial pressure.
In the absence of measurements of cardiac output, hypotensive patients with severe sepsis may have low, normal, or increased cardiac outputs. Therefore, treatment with a combined inotrope/vasopressor such as norepinephrine or dopamine is recommended. When the capability exists for monitoring cardiac output in addition to blood pressure, a vasopressor such as norepinephrine and an inotrope such as dobutamine may be used separately to target specific levels of mean arterial pressure and cardiac output.
(Level I) A strategy of increasing cardiac index to achieve an arbitrarily predefined elevated level is not recommended – large prospective clinical trials that included ICU patients with sepsis failed to demonstrate benefit from increasing oxygen delivery to supranormal levels by use of dobutamine (NEJM 333: 1025, 1995). The goal of resuscitation should instead be to achieve adequate levels of oxygen delivery or avoid flow-dependent tissue hypoxia.
Blood Product Administration
(Level I) Once tissue hypoperfusion has resolved and in the absence of extenuating circumstances, such as significant coronary artery disease (questionable), acute hemorrhage, or lactic acidosis, transfuse only when hemoglobin <7.0 g/dL to a target of 7.0–9.0 g/dL. Red blood cell transfusion in septic patients increases oxygen delivery but does not usually increase oxygen consumption (Crit Care Med 21: 1312, 1993). This transfusion threshold contrasts with the target of a hematocrit of 30% in patients with low central venous oxygen saturation during the first 6 hrs of resuscitation of septic shock.
(Level I) Erythropoietin is not recommended as a specific treatment of anemia associated with severe sepsis but may be used when septic patients have other accepted reasons such as renal failure induced compromise of red blood cell production. Clinical trials in critically ill patients show some decrease in red cell transfusion requirement with no effect on clinical outcome.
(Level III or IV) Routine use of fresh frozen plasma to correct laboratory clotting abnormalities in the absence of bleeding or planned invasive procedures is not recommended. Professional organizations have recommended fresh frozen plasma for coagulopathy when there is a documented deficiency of coagulation factors and the presence of active bleeding or before surgical or invasive procedures.
(Level I) Antithrombin administration is not recommended for the treatment of severe sepsis and septic shock (JAMA 286: 1869, 2001).
(Level III or IV) In patients with severe sepsis, platelets should be administered when counts are < 5000/mm3 regardless of apparent bleeding. Platelet transfusion may be considered when counts are 5000–30,000/mm3 and there is a significant risk of bleeding.
Mechanical Ventilation of Sepsis-Induced Acute Lung Injury (ALI)/ARDS
(Level I) As a starting point, use 6 mL per kilogram of predicted body weight as a goal in conjunction with the goal of maintaining end inspiratory plateau pressures < 30 cm H2O.
(Level II) Permissive hypercapnia can be tolerated in patients with ALI/ARDS if required to minimize plateau pressures and tidal volumes. The use of hypercarbia is limited in patients with preexisting metabolic acidosis and is contraindicated in patients with increased intracranial pressure. Sodium bicarbonate infusion may be considered in select patients to facilitate use of permissive hypercarbia [Crit Care Med 22: 1568, 1994]
(Level IV or V) A minimum amount of PEEP pressure should be set to prevent lung collapse at end-expiration. Setting PEEP based on severity of oxygenation deficit and guided by the FiO2 required to maintain adequate oxygenation is one acceptable approach. Some experts titrate PEEP according to bedside measurements of thoracopulmonary compliance (to obtain the highest compliance, reflecting lung recruitment).
(Level IV or V) In facilities with experience, prone positioning should be considered in ARDS patients requiring potentially injurious levels of FiO2 or plateau pressure who are not at high risk for adverse consequences of positional changes Rationale. Several smaller studies have shown that a majority of patients with ALI/ARDS respond to the prone position with improved oxygenation. The large multiple-center trial of prone positioning for ~ 7 hrs/day did not show improvement in mortality rates but suggested improvement in those patients with the most severe hypoxemia by PaO2/FIO2 ratio [NEJM 345: 568, 2001]. Prone positioning may be associated with potentially life-threatening complications, including accidental dislodgment of the endotracheal tube and central venous catheters, but these complications can usually be avoided.
(Level II) Unless contraindicated, mechanically ventilated patients should be maintained with the head of the bed raised to 45° to prevent the development of ventilator-associated pneumonia [Lancet 345: 1851, 1999]
(Level I) Mechanically ventilated patients should undergo a spontaneous breathing trial to evaluate the ability to discontinue ventilation when they satisfy the following criteria: a) arousable; b) hemodynamically stable (without vasopressor agents); c) no new potentially serious conditions; d) low ventilatory and end-expiratory pressure requirements; and e) requiring levels of FiO2 that could be safely delivered with a face mask or nasal cannula. If the spontaneous breathing trial is successful, consideration should be given for extubation. Spontaneous breathing trial options include a low level of pressure support with continuous positive airway pressure 5 cm H2O or a T-piece. Recent studies demonstrate that daily spontaneous breathing trials reduce the duration of mechanical ventilation [Am J Resp Crit Care Med 159: 512, 1999]
Sedation, Analgesia, and Neuromuscular Blockade in Sepsis
(Level I) Protocols should be used when sedation of critically ill mechanically ventilated patients is required. The protocol should include the use of a sedation goal, measured by a standardized subjective sedation scale.
(Level I) Either intermittent bolus sedation or continuous infusion sedation to predetermined end points (e.g., sedation scales) with daily interruption/lightening of continuous infusion sedation with awakening and retitration, if necessary, are recommended methods for sedation administration. The use of sedation protocols in mechanically ventilated patients has shown a reduced duration of mechanical ventilation, length of stay, and tracheostomy rates [Crit Care Med 27: 2609, 1999]
(Level IV or V) Neuromuscular blockers should be avoided if at all possible in the septic patient due to the risk of prolonged neuromuscular blockade.
(Level III) Following initial stabilization of patients with severe sepsis, maintain blood glucose from 80 – 110 mg/dL with continuous infusion of insulin and glucose. With this protocol, glucose should be monitored frequently after initiation of the protocol (every 30 – 60 mins) and on a regular basis (every 4 hrs) once the blood glucose concentration has stabilized. [NEJM 345: 1359, 2001]
(Level IV or V) In patients with severe sepsis, a strategy of glycemic control should include a nutrition protocol with the preferential use of the enteral route.
(Level I) In acute renal failure, and in the absence of hemodynamic instability, continuous venovenous hemofiltration and intermittent hemodialysis are considered equivalent. Continuous hemofiltration offers easier management of fluid balance in hemodynamically unstable septic patients. Intermittent hemodialysis may be poorly tolerated in hemodynamically unstable patients.
(Level II) Bicarbonate therapy for the purpose of improving hemodynamics or reducing vasopressor requirements is not recommended for treatment of hypoperfusion-induced lactic acidemia with pH > 7.15 [Ann Int Med 112: 492, 1990]. The effect of bicarbonate administration on hemodynamics and vasopressor requirement at lower pH as well as the effect on clinical outcome at any pH has not been studied.
Deep Vein Thrombosis Prophylaxis
(Level I) Severe sepsis patients should receive deep vein thrombosis (DVT) prophylaxis with either low-dose unfractionated heparin or LMWH. For septic patients who have a contraindication for heparin use (i.e., thrombocytopenia, severe coagulopathy, active bleeding, recent intracerebral hemorrhage), the use of a mechanical prophylactic device is recommended (unless contraindicated by the presence of peripheral vascular disease). In very high-risk patients such as those who have severe sepsis and history of DVT, a combination of pharmacologic and mechanical therapy is recommended.
Stress Ulcer Prophylaxis
(Level I) Stress ulcer prophylaxis should be given to all patients with severe sepsis. H2 receptor inhibitors are more efficacious than sucralfate and are the preferred agents. Proton pump inhibitors have not been assessed in a direct comparison with H2 receptor antagonists and, therefore, their relative efficacy is unknown.
Steroid Replacement Therapy
(Level II) Intravenous corticosteroids are recommended in patients with septic shock who, despite adequate fluid replacement, require vasopressor therapy to maintain adequate blood pressure. In 2008 this was amended to only include patients who are refractory to both vasopressors and fluids
Data Underpinning Steroid Recommendations
Patients with documented SIRS, infection, and shock (SBP < 90, UOP < 0.5 mL/kg for 1 hour, PaO2/FiO2 < 280, and on the vent, MI, PE, advanced cancer excluded) who responded to 250 g tetracosactrin by < 9 µg /dL change in cortisol showed a 22% increase in survival at 28 days when given 50 mg IV hydrocortisone q6h and 50 µg fludocortisone qday for 7 days. Survival in non-responders was statistically insignificant, as was survival in both groups at 1 year. [JAMA 288: 862, 2002]
Note that the results of Annane et al’s study, which showed a significant reduction in the risk of death in septic patients deemed to be hypoadrenal (hazard ratio 0.67, 95% CI 0.47-0.95, p =0.02) [Annane D et al. JAMA 288: 862, 2002] were not replicated by Sprung et al. in the CORTICUS trial [Sprung CL et al. NEJM 358: 111, 2008]. Note that the CORTICUS trial used hydrocortisone only (Annane et al. used hydrocortisone and fludrocortisone) and had less restrictive entry criteria (the patients were not as sick), but did show an increase in the incidence of resistant infections in the steroid group
Glucocorticoid / Mineralocorticoid Activity
Glucocorticoid / Mineralocorticoid Potency
- Hydrocortisone: 1:1 (8h duration) – note that this is the synthetic version of cortisol
- Prednisone: 4:0.8 (16-36h duration) – less mineralocorticoid activity than hydrocortisone
- Methylprednisolone: 6:0.5 (18-40h duration) – MUCH less mineralocorticoid activity than hydrocortisone
- Dexamethasone: 60:0 (36-54h duration) – NO mineralocorticoid activity
- Fludrocortisone: 15:200 (24h duration) – predominantly mineralocorticoid activity
(see also Adrenal Function)
(Level III or IV) Clinicians should not wait for ACTH stimulation results to administer corticosteroids. In patients with septic shock, clinicians should consider administering a dose of dexamethasone until such time that an ACTH stimulation test can be administered because dexamethasone, unlike hydrocortisone, does not interfere with the cortisol assay. There has been no comparative study between a fixed duration and clinically guided regimen. Two RCTs used a fixed duration.
(Level I) Doses of corticosteroids > 300 mg hydrocortisone daily should not be used in severe sepsis or septic shock for the purpose of treating septic shock, as it is ineffective or harmful (NEJM 317: 659, 1987).
(Level III or IV) In the absence of shock, corticosteroids should not be administered for the treatment of sepsis. There is, however, no contraindication to continuing maintenance steroid therapy or to using stress dose steroids if the patient’s history of corticosteroid administration or the patient’s endocrine history warrants.
Wang et al. conducted a systematic review and several meta-analyses of the literature in 2014 and concluded that low-dose hydrocortisone therapy ameliorates septic shock at 7 and 28 days, it does not reduce 28-day mortality (Anesth Analg 2014;118:346–57).
Intravenous Immunoglobulin (IVIG)
In a metaanalysis including 2202 patients in 27 trials, Kreymann et al suggest that polyvalent immunoglobulins significantly reduce mortality in adults with sepsis (RR 0.79, CI 0.69-0.90) [Kreymann KG et al. CCM 35: 2677, 2007]. The largest trial in this metaanalysis included 221 patients. Werdan et al. conducted a prospective, multicenter, randomized controlled trial in which IVIG was administered to based on APACHE II score (n = 653), finding no mortality difference at 28 days (37.3% vs. 39.3% in the treatment group, p = 0.67) [Werdan K et al. 35: 2693, 2007]. Despite this negative study, Laupland et al. examined the use of IVIG in fourteen RCTs (including Werdan’s), and did find a reduction in mortality in adult patients with severe sepsis (OR 0.66, CI 0.53-0.83) [Laupland KB et al. CCM 35: 2686, 2007].
Based on Laupland’s metaanalysis, it appears that a positive effect of IVIG is more likely in older, smaller studies. Larger, more recent studies are less likely to show a significant effect [Laupland KB et al. CCM 35: 2686, 2007]. With the exception of Werdan et al., the lack of large, high quality studies makes it difficult to justify the administration of IVIG in severe sepsis based on available data.
Recombinant Human Activated Protein C (rhAPC)
Based on a single prospective randomized controlled trial [NEJM 344: 699, 2001], rhAPC was at one point given a Level I recommendation in patients at high risk of death (APACHE II >=25, sepsis-induced multiple organ failure, septic shock, or sepsis-induced ARDS) and with no absolute contraindication related to bleeding risk or relative contraindication that outweighs the potential benefit of rhAPC (active internal bleeding, hemorrhagic stroke within 3 mos., intracranial or intraspinal surgery, or severe head trauma within 2 mos., trauma with an increased risk of life-threatening bleeding, epidural catheter, intracranial neoplasm or mass lesion or evidence of cerebral herniation). However, based on the PROWESS-SHOCK trial (n = 1696, mortality 26.4% versus 24.2% in controls), Eli Lilly & Co. have withdrawn rhAPC (Xigris) from the market and thus it is no longer a treament option.
Children normally have a lower blood pressure than adults and can prevent reduction in blood pressure by vasoconstriction and increasing heart rate. Therefore, blood pressure by itself is not a reliable end point for assessing the adequacy of resuscitation. Hepatomegaly occurs in children who are fluid overloaded.
Due to low FRC, young infants and neonates with severe sepsis may require early intubation. In premature infants, additional attention is paid to avoiding hyperoxemia to prevent retinopathy.
IV access is more difficult to attain in children. However, it is accepted that aggressive fluid resuscitation is of fundamental importance to survival of septic shock in children. A study of dengue shock in children showed lactated Ringer’s to be superior to saline or other fluids (although colloids trended to be better in those with narrow pulse pressure). Fluid infusion is best initiated with boluses of 20 mL/kg over 5–10 mins, titrated to clinical monitors of cardiac output, including heart rate, urine output, capillary refill, and level of consciousness.
Dopamine is the first choice of support for the pediatric patient with hypotension refractory to fluid resuscitation. Dopamine-refractory shock may reverse with epinephrine or norepinephrine infusion.
Therapeutic end points are capillary refill of <2 secs, normal pulses with no differential between peripheral and central pulses, warm extremities, urine output >1 mL•kg-1•hr-1, normal mental status, decreased lactate and increased base deficit, and superior vena cava or mixed venous oxygen saturation >70%. As noted previously, blood pressure by itself is not a reliable end point for resuscitation. If a pulmonary artery catheter is used, therapeutic end points are cardiac index > 3.3 and < 6.0 L•min-1•m-2 with normal perfusion pressure.
Hydrocortisone therapy should be reserved for use in children with catecholamine resistance and suspected or proven adrenal insufficiency. Adrenal insufficiency in the case of catecholamine-resistant septic shock is assumed at a random total cortisol concentration < 18g/dL or with a post ACTH stimulation test increase in cortisol of <9 g/dL (248 nmol/L).
No randomized studies using rhAPC have been performed. There has been one dose finding, placebo-controlled study performed using protein C concentrate. This study was not powered to show an effect on mortality rate but did show a positive effect on sepsis-induced coagulation disturbances.
Growth factors or white blood cell transfusions are given to patients with neutropenic sepsis secondary to chemotherapy or white blood cell primary immune deficiency. A randomized, controlled trial showed improved outcomes in neonates with sepsis and an absolute neutrophil count <1500/L treated with a 7-day course of GMCF.
Most DVTs in young children are associated with central venous catheters (occurs in approximately 25% of children with a femoral central venous catheter). There are no data on use of heparin prophylaxis to prevent DVT in children.
No studies have been performed in children analyzing the effect of stress ulcer prophylaxis. Stress ulcer prophylaxis strategy is commonly used in mechanically ventilated children, usually with H2 blockers. Its effect is not known.
Continuous venovenous hemofiltration may be clinically useful in children with anuria/severe oliguria and fluid overload, but no large RCTs have been performed.
In general, infants are at risk for developing hypoglycemia when they depend on intravenous fluids. This means that a glucose intake of 4 – 6 mg•kg-1•min-1 or maintenance fluid intake with glucose 10% in NaCl 0.45% is advised. There are no studies in pediatric patients analyzing the effect of rigid glycemic control using insulin. This should only be done with frequent glucose monitoring in view of the risks for hypoglycemia.
In the absence of data, it is reasonable to maintain hemoglobin concentration within the normal range for age in children with severe sepsis and septic shock (>10 g/dL).
Polyclonal IVIG has been reported to reduce mortality rate and is a promising adjuvant in the treatment of sepsis and septic shock. In children, however, all the trials have been small, and the totality of the evidence is insufficient to support a robust conclusion of benefit. Adjunctive therapy with monoclonal intravenous immunoglobulins remains experimental.
ECMO has been used in septic shock in children, but its impact is not clear.
Survival from refractory shock or respiratory failure associated with sepsis is 80% in neonates and 50% in children. There is one study analyzing 12 patients with meningococcal sepsis on ECMO; eight of the 12 patients survived, with six leading functionally normal lives at a median of 1 yr (range, 4 months to 4 yrs) of follow-up. Children with sepsis on ECMO do not perform worse than children without sepsis at long-term follow-up.