Introduction
In response to infection, various self-defense mediators are released. These mediators dilate peripheral vessels, resulting in a relative decrease in intravascular volume. As such, the treatment strategy for septic shock is focused on early-stage control of infection (administering antimicrobials, gaining control of infected lesions) and appropriate control of circulation (improving cardiac output and oxygen supply, managing tissue hypoperfusion).
According to a meta-analysis assessing goal-directed therapy (GDT) that set target values and circulatory management for septic shock, the mortality rate was not reduced by achieving the goals alone, but was reduced if the goal was achieved within 6 hours [108]. Stated differently, time is a critical factor with respect to the effectiveness of initial resuscitation in septic shock. The early goal-directed therapy (EGDT) capable of improving tissue hypoperfusion within 6 h introduced by Rivers et al. [109] was strongly recommended in both the Surviving Sepsis Campaign Guidelines (SSCG) 2012 [29] and the Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock (1st edition) [2]. However, the three large-scale randomized controlled trials (RCTs) (Protocolized Care for Early Septic Shock (ProCESS) [110], Australasian Resuscitation in Sepsis Evaluation (ARISE) [111], and Protocolised Management in Sepsis (ProMISe) [112]) subsequently reported in 2014 and 2015 failed to demonstrate the usefulness of EGDT. As such, the guideline committee for this clinical question (CQ) conducted a systematic review based on the question, “CQ7-1: Is EGDT recommended for initial resuscitation in patients with sepsis or septic shock?” The EGDT discussed herein refers to the resuscitation method proposed by Rivers et al. [109] (calling for initial fluid resuscitation and administration of vasoconstrictors with the goal of achieving a central venous pressure (CVP) of 8–12 mmHg, mean arterial pressure ≥ 65 mmHg, urine volume ≥ 0.5 mL/kg/h, and ScvO2 ≥ 70% within 6 h).
A detailed assessment of these RCTs [110,111,112] revealed that large-volumes of fluid (crystalloid solution 30 mL/kg or more) had already been given before protocol initiation. Therefore, the guideline committee for this CQ concluded that the methods of initial fluid resuscitation should be assessed separately from the EGDT intervention, and the next CQ was presented, “CQ7-2: What volume of fluid should be given in the initial resuscitation of patients with septic shock?”
Septic shock may be attributed not only to a relative decrease in intravascular volume associated with vasodilatation but also to a type of cardiomyopathy known as sepsis-induced myocardial dysfunction (SIMD) [113, 114]. Therefore, “CQ7-3: Should cardiac function be assessed using echocardiography when initiating fluid resuscitation in sepsis?” was presented, but no RCT conforming to the Patients, Intervention, Comparison, Outcome (PICO) process was found for this CQ.
The following two CQs were presented with regard to the fluid of choice for initial resuscitation and subsequent intravascular volume replacement in patients with septic shock, “CQ7-4: Should a crystalloid solution or an artificial colloidal solution be used in the initial fluid resuscitation?” and “CQ7-5: Should albumin solution be used during the initial resuscitation fluid in septic shock?” During the first public comment for CQ7-5, it was pointed out that the directions of the recommendations offered and the results of the accompanying systematic review regarding mortality rate appeared to differ. The guideline committee reevaluated the evidence originating from the RCTs conforming to the PICO process only and found a slight improvement in survival associated with albumin administration. However, the strength of this evidence was considered to be weak, and albumin use in this context was found to have only a limited effect. The strength of the recommendation offered was determined by considering the potential for complications such as unknown infections and allergies caused by blood products. However, because the situations differ for patients requiring substantial amounts of crystalloids until shock recovery and those who develop hypoalbuminemia, we considered it necessary to deal with them separately and added an expert consensus.
With respect to monitoring during initial resuscitation, the following question, “CQ7-6: What method should be used to predict fluid responsiveness during initial resuscitation?” was presented, and five RCTs conforming to the PICO process were analyzed. There were four interventions involving assessment through passive leg raising (PLR), one intervention involving assessment through transpulmonary thermodilution, and two interventions (including redundancies) involving assessment through stroke volume variation (SVV). While a meta-analysis was performed for each method of assessment, the meta-analysis conducted for this CQ was unable to show any improvement in prognosis. The intrathoracic blood volume index obtained through the pulmonary thermodilution method [115] as well as dynamic parameters such as SVV and pulse pressure variation have been reported to be more useful for the prediction of fluid response than CVP [116]. However, caution is warranted when interpreting these findings, as test reliability is poor in patients with arrhythmias such as atrial fibrillation, patients with spontaneous respiration, and patients with restrictions in tidal volume during mechanical ventilation due to acute respiratory distress syndrome. PLR also has poor reliability in patients with elevated intra-abdominal pressure [117].
The practice guidelines reported so far [2, 29] have highlighted the importance of measuring lactate levels as a marker of tissue hypoperfusion. This guideline also presents the following CQs, “CQ7-7: Should lactate levels be used as an indicator during initial resuscitation in sepsis?” and “CQ7-8: ScvO2 or lactate clearance: which is more useful as an indicator of initial resuscitation?” A systematic review was performed on the above CQs, but since only one RCT conforming to the PICO process could be found (Jones et al. [118]), it was judged that offering guidance at the recommendation level would be difficult for these CQs.
Regarding cardiovascular agents used in the management of septic shock, we considered two kinds of cardiovascular agents, vasopressors (dopamine, noradrenaline, adrenaline, vasopressin), and an inotropic drug (dobutamine). A systematic review and meta-analysis were performed for the CQ “CQ7-9: Noradrenaline or dopamine: which should be used as a first-line vasopressor to treat patients with septic shock that are unresponsive to initial fluid resuscitation?” In addition, the subsequent two CQs are presented to address situations where noradrenaline use does not achieve a sufficient increase in blood pressure, “CQ7-10: Should adrenaline be used in septic shock when noradrenaline fails to improve the blood pressure?” and “CQ7-11: Should vasopressin be used in patients with septic shock who fail to achieve the target blood pressure despite the use of noradrenaline?”
Because the difference between the usage of adrenaline and vasopressin has not been established in the contents of the above CQ and an expert consensus, a brief supplement is provided on this topic. In septic shock, despite appropriate fluid resuscitation and noradrenaline administration, the following factors can create difficulty in maintaining hemodynamics: (1) difficulty in controlling peripheral vascular resistance accompanying vasodilatation (relative hypovolemic shock) [119] and (2) cardiac dysfunction associated with SIMD (cardiogenic shock) [113, 114]. These pathologies can be distinguished relatively easily through echocardiography. Administering adrenaline as well as a small amount of vasopressin (0.03 units/min) and noradrenaline is effective for patients exhibiting relative circulating hypovolemic shock (vasodilatory shock). On the other hand, in cases of cardiogenic shock, administering adrenaline to obtain a cardiac contractile potentiating effect (β1-receptor stimulating action) can be effective, but administering vasopressin, which does not yield this effect, may cause further exacerbation of this pathological state leading to cardiogenic shock. For these reasons, appropriate vasopressors should be selected after assessing cardiac preload and contractility via techniques such as echocardiography in septic shock.
Meanwhile, it has been reported that in septic shock, intracellular signaling mediated by β1 adrenergic receptors is impaired due to early-phase pro-inflammatory cytokines, impeding the ability of dobutamine to improve cardiac function [120, 121]. As such, with respect to dobutamine, an inotropic drug, the following CQ, “CQ7-12: Should dobutamine be used in patients with septic shock who show evidence of cardiac dysfunction?” was presented and a systematic review was conducted. The 28-day mortality rate in the RCTs [122, 123] was 41.9% in the control group (adrenaline group) and 36.7% in the intervention group (dobutamine group) (p = 0.31), and dobutamine was demonstrated to be comparable or non-inferior to adrenaline. According to the SSCG 2012 [29], dobutamine use is recommended (grade 1C) (a) when cardiac function is declining and (b) in amounts of up to 20 μg/kg/min when low perfusion persists despite adequate fluid resuscitation. However, the Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock (1st edition) [2] states that, “As improvement of reduced cardiac function is difficult to achieve with dobutamine in septic shock, combined administration with a phosphodiesterase III inhibitor or a calcium sensitivity enhancer should be considered as an alternative.” One RCT (the LeoPARDS (Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis) trial) to evaluate calcium sensitivity enhancers in patients with sepsis was performed recently, but no prognostic improvement effect was observed [124]. It was determined that the quality of the evidence supporting the recommendation of these drugs is currently poor, and accordingly, this guideline does not include a CQ on their use. Meanwhile, regarding the usefulness of β-blockers in septic shock, Morelli et al. [125] conducted an RCT evaluating ultra-short-acting β-blockers, and Wang et al. [126] conducted an RCT investigating the efficacy of combination therapy of an ultra-short-acting β-blocker and a phosphodiesterase III inhibitor. In both of these studies, it was found that the use of β-blockers resulted in a reduced mortality rate, suggesting the possibility that β-blockers may have effects beyond rate control. However, for reasons such as the fact that the evidence supporting the usefulness of β-blockers in septic shock is still somewhat controversial [127], this guideline does not include a CQ regarding their use.
The recommendations and expert consensus concerning initial resuscitation and cardiovascular agents with respect to septic shock presented in this guideline are based on the RCTs and/or systematic reviews that have been reported so far. However, the treatment of sepsis can vary significantly depending on the level of care offered by a given facility and the level of knowledge and skills of the attending physician and staff. This guideline related to sepsis and septic shock should be used wisely with these things in mind. Time is a critical factor with respect to the effectiveness of initial resuscitation and cardiovascular agents in septic shock, and it is important to fully understand that “sepsis is an emergency” and to treat patients with septic shock promptly.
CQ7-1: Is EGDT recommended for initial resuscitation in patients with sepsis or septic shock?
Answer (recommendation)
We suggest against the use of EGDT when performing initial resuscitation in patients with sepsis or septic shock (2A) (rate of agreement, 100%).
Rationale
Three RCTs [110,111,112] conforming to the PICO process were identified based on a search of the PubMed database and were used in the final analysis for this CQ. Regarding the 90- and 28-day mortality rates, EGDT was not effective in improving mortality rate in comparison to the standard treatment (90-day mortality rate: risk ratio 0.98 (95% confidence interval (CI) 0.88–1.10); 28-day mortality rate: risk ratio 0.98 (95% CI 0.84–1.13)). The time to shock reversal was not assessed by any RCT. Regarding intensive care unit (ICU) length of stay, the mean difference (MD) was 0.27 (95% CI − 0.33–0.87) in the comparison between the EGDT group and the standard treatment group, and no significant difference was observed.
Regarding the benefit-risk balance, no improvement in mortality rate as a result of complying with EGDT was observed in comparison to the standard treatment. In addition, no shortening of ICU length of stay as a result of complying with EGDT was observed (MD 0.27 (95% CI − 0.33–0.87)), and no benefit of EGDT over the standard treatment could be found. However, dobutamine dosages and the quantity of blood transfused increased significantly in the EGDT group [110, 111], and due to the increased frequency of arrhythmias associated with dobutamine, greater overall risk of side effects associated with transfusions, and increased time and quantity of work required of hospital staff, it is possible that compliance with EGDT may increase the risk of harm (burden) faced by patients. Based on the above, it was determined that the potential harms presented by EGDT likely outweigh its potential benefits.
CQ7-2: What volume of fluid should be given in initial resuscitation in septic shock?
Answer (opinion)
We suggest that 30 mL/kg or more of an extracellular fluid replacement solution is administrated when performing initial fluid resuscitation in patients with septic shock with a relative decrease in intravascular volume associated with vasodilatation (expert consensus/no evidence) (rate of agreement, 100%).
Comment: 30 mL/kg or more of an extracellular fluid replacement solution should be administered after assessing the decrease in intravascular volume.
Rationale
No RCTs applicable to this CQ could be found as a result of a search of the PubMed database. As such, it was concluded that an expert consensus should be offered, as the evidence for this CQ is inadequate to support a recommendation. In addition, in three large-scale RCTs evaluating the effectiveness of EGDT (ProCESS [110], ARISE [111], and ProMISe [112]), when the differences in intergroup (EGDT group vs. standard treatment group) total volume of fluid transfused prior to study protocol initiation were calculated, the following differentials were revealed: ProCESS (2.3 ± 1.5 L vs. 2.1 ± 1.4 L), ARISE (2.5 ± 1.2 L vs. 2.6 ± 1.3 L), and ProMISe (1.9 ± 1.1 L vs. 2.0 ± 1.1 L). All the subjects had already received over 30 mL/kg of crystalloid solution during the initial resuscitation prior to group assignment.
Regarding the benefit-risk balance, the concept of large-volume initial fluid resuscitation (infusion of 30 mL/kg or 2000 mL within approximately 1 h) became recognized as a common sense approach based on the conventional guidelines, and there is a possibility that the prognosis of patients with sepsis may be improved by supplementing the relative decrease in intravascular volume associated with vasodilatation and optimizing the balance of tissue oxygen supply and demand as quickly as possible.
On the other hand, excessive extracellular fluid replacement may cause a deterioration in cardiac function (heart failure) and pulmonary function (pulmonary edema). Frequent assessment of hemodynamics is necessary to avoid excessive volume loading, which may increase the burden on medical staff. The cost of extracellular fluid replacement solution may be a burden on the intervention group but is relatively low. Based on the above considerations, it was concluded that the benefits of administering 30 mL/kg or more of an extracellular fluid replacement solution during the initial resuscitation in septic shock clearly outweigh the potential risks.
CQ7-3: Should cardiac function be assessed using echocardiography when initiating fluid resuscitation in sepsis?
Answer (opinion)
We suggest the cardiac function using echocardiography is assessed when initiating fluid resuscitation in patients with sepsis (expert consensus/no evidence) (rate of agreement, 100%).
Comment: The assessment of cardiac function using echocardiography discussed in this CQ indicates the simple evaluation of cardiac function performed at the bedside. It is focused on cardiac function (movement of the heart), and measurements related to vascular (inferior vena cava diameter, intracardiac volume) intended to afford an approximate assessment of intravascular volume prior to initiating resuscitation. It is desirable that all physicians, and not just cardiologists, involved in the resuscitation of patients with sepsis be proficient with this technique.
Rationale
Although a literature search was conducted to identify RCTs examining whether the assessment of cardiac function using echocardiography affects the prognosis of patients with sepsis undergoing initial resuscitation, no RCTs pertaining to this CQ could be found. Therefore, it was concluded that an expert consensus should be offered as the evidence for this CQ is inadequate to support a recommendation.
Regarding the benefit-risk balance, although no supporting evidence could be found, assessing cardiac function and intravascular volume using echocardiography when initiating resuscitation in patients with sepsis is useful in determining the infusion rate and in catecholamine selection. Therefore, it is believed that conducting this assessment will lead to more appropriate fluid resuscitation and drug administration. Echocardiography assessment is simple and non-invasive, and little patient burden for physicians is associated with the intervention itself. In institutions that do not routinely use echocardiography for assessment, the use of this technique will require additional time and may contribute to delays in initiating resuscitation. In addition, the price of most echocardiography devices is in the range of several million yen (approximately USD 77,000), and thus, the financial burden placed on facilities will be substantial when purchasing a new device. However, such devices have high versatility, are believed to be adequate for their desired uses, and are cost-effective. Therefore, it was concluded that the benefits of assessing cardiac function using echocardiography when initiating resuscitation in patients with sepsis clearly outweigh the potential harms.
CQ7-4: Should a crystalloid solution or an artificial colloidal solution be used in the initial fluid resuscitation?
Answer (recommendation)
We suggest against the use of an artificial colloidal solution during the initial resuscitation of patients with sepsis or septic shock (2B) (rate of agreement, 89.5%).
Rationale
Nine RCTs [128,129,130,131,132,133,134,135,136] were identified as a result of the systematic review [137] conducted for this CQ. The effect of infusing an artificial colloidal solution on the risk ratios for the different mortality rates examined were as follows: ICU mortality rate, 0.56 (95% CI 0.34–0.94); 28-day mortality rate, 1.11 (95% CI 0.96–1.28); and 90-day mortality rate, 1.14 (95% CI 1.04–1.26). The impact on other risk ratios examined was as follows: acute kidney injury (AKI) incidence risk ratio, 1.32 (95% CI 1.09–1.60); renal replacement therapy (RRT) performance risk ratio, 1.46 (95% CI 1.21–1.77); red blood cell (RBC) transfusion risk ratio, 1.19 (95% CI 1.04–1.36); and fresh frozen plasma transfusion risk ratio, 1.18 (95% CI 0.94–1.49). Although ICU mortality rate decreased because of artificial colloidal solution use, the 90-day mortality rate, AKI incidence rate, RRT performance rate, and the RBC transfusion rate each increased significantly.
Regarding the benefit-risk balance, it is difficult to determine whether mortality rate will improve by using an artificial colloidal solution during the initial fluid resuscitation, as the AKI incidence risk ratio, the RRT performance risk ratio, and the RBC transfusion risk ratio each increased significantly. The cost of artificial colloidal solutions is higher than crystalloid solutions and may cause allergies, which can place an additional burden on the intervention group. Based on the above, it was determined that the potential harms associated with the use of artificial colloidal solution likely outweigh the potential benefits.
CQ7-5: Should albumin solution be used during the initial resuscitation in septic shock?
Answer (recommendation and opinion)
We suggest against the routine use of albumin solution during the initial resuscitation of patients with sepsis (2C).
The administration of albumin solution may be considered when large volumes of crystalloid solution are required for resuscitation, or when hypoalbuminemia is observed (expert consensus/no evidence) (rate of agreement, 94.7%).
Rationale
A search of the PubMed database was conducted using the keywords “sepsis,” “septic shock,” and “albumin.” Five systematic reviews and one new RCT (CRISTAL (Colloids Versus Crystalloids for the Resuscitation of the Critically Ill) trial [138]) were extracted. The systematic reviews [139] and RCT [138] found using the most recent literature search period and that scored highly on the AMSTAR (A Measurement Tool to Assess Systematic Reviews) measurement tool (9 points) were adopted as high-quality studies for this CQ.
Among these studies, only the SAFE (Saline Versus Albumin Fluid Evaluation) 2011 study [140] was identified as an applicable RCT. No significant difference between the mortality risk ratio of 0.87 (95% CI 0.74–1.02) and ICU length of stay of 0.7 (95% CI − 0.10–1.50) was observed. No assessment was carried out regarding time to shock reversal.
Regarding the benefit-risk balance, although there was a tendency for a decrease in mortality rate, no significant difference was observed between the albumin and control groups. In addition, several complications, including infection and allergic reactions, may occur following albumin administration. Based on these findings, the potential risks for the albumin use as a standard resuscitation fluid likely outweighed the potential benefits.
CQ7-6: What method should be used to predict fluid responsiveness during initial fluid resuscitation?
Answer (opinion)
We suggest that the combination of multiple monitoring methods is used while considering the limitations of each indicator, for predicting fluid responsiveness during initial fluid resuscitation in patients with sepsis and septic shock (expert consensus/quality of evidence “C”) (rate of agreement, 94.7%).
Comment: The evidence was insufficient to support the recommendation of specific monitoring techniques to be used during initial resuscitation in patients with sepsis and septic shock.
Rationale
Two hundred seventy reports were identified as a result of a search for studies assessing survival in sepsis and septic shock patients who had undergone initial fluid resuscitation using various monitoring methods. After primary and secondary screening, five RCTs were extracted and used in the analysis [141,142,143,144,145]. Four RCTs included evaluation of PLR, one for transpulmonary thermodilution, and two for SVV; a meta-analysis was performed for each evaluation method.
No significant effect on the defined outcomes for analysis (mortality rate, ICU length of stay, time to shock reversal) was observed for these three evaluation methods. The monitoring methods used in the control group also varied and “performance of initial resuscitation without use of a specific monitoring method” established as the control for PICO (C) was not adopted. Therefore, it was determined that a serious issue regarding indirectness existed. Because of the difficulty in implementing study blinding, small sample size, the risk of bias, and various inaccuracies, the quality of the study was lowered, and the strength of this evidence was classified as weak (C) or very weak (D). Based on these findings, it was decided that the current evidence was not sufficient to support a recommendation and that an opinion (expert consensus) would be presented.
Regarding the benefit-risk balance, central venous catheters and arterial catheters are indwelled in most cases, and the use of some form of monitoring and optimization of infusion volume can result in improved prognosis. Therefore, it was concluded that the benefits of predicting fluid responsiveness during initial resuscitation likely outweigh the potential harms.
CQ7-7: Should lactate levels be used as an indicator during initial resuscitation in sepsis?
Answer (opinion)
We suggest that lactate levels over time are used when performing initial resuscitation in patients with sepsis (expert consensus/no evidence) (rate of agreement, 94.7%).
Rationale
Primary and secondary screening of literature (174 sources) obtained after a search was conducted. As no RCTs applicable to this CQ (comparing lactate levels over time during initial resuscitation in sepsis) could be found, it was decided that an expert consensus would be presented instead of a recommendation.
Regarding the benefit-risk balance, lactate levels are associated with the patient’s prognosis in sepsis, and measuring lactate levels can aid in identifying critically ill patients. In addition, according to a report by Jansen et al., as a result of comparing patients with a lactate level of 3.0 mEq/L or higher (proportion of patients with sepsis was approximately 40% in both groups) to a comparator group that underwent initial therapy with lactate clearance as an indicator, no significant difference in in-hospital mortality rate was observed in a univariate analysis. However, in a multivariate analysis, in-hospital mortality rate improved in the group in which lactate clearance was used as an indicator [146]. Therefore, performing initial resuscitation while monitoring and assessing lactate levels over time may improve patient’s prognosis in sepsis. Arterial punctures and invasive arterial catheter insertion may also cause mechanical complications such as hematoma and embolism as well as infection, and in order to confirm lactate clearance, frequently measuring and analyzing blood gas content during initial resuscitation becomes necessary. However, as monitoring through an arterial catheter is believed to be performed in many patients, the quantity of blood collected per measurement is small, and the burden on patients appears to be minimal. Therefore, it was concluded that the potential benefits of the use of lactate levels as an indicator during initial resuscitation clearly outweigh the potential harms.
CQ7-8: ScvO2 or lactate clearance: Which is more useful as an indicator of initial resuscitation?
Answer (opinion)
Either ScvO2 or lactate clearance may be used as indicators of initial resuscitation (expert consensus/quality of evidence “D”) (rate of agreement, 94.7%).
Rationale
Only one RCT (Jones et al. [118]) comparing ScvO2 and serum lactate values was identified, and there was no significant difference in in-hospital mortality rates between using ScvO2 and lactate clearance to guide initial resuscitation.
Regarding the benefit-risk balance, a specific central venous catheter is needed for continuous ScvO2 monitoring. Collecting blood samples to evaluate ScvO2 or lactate levels may increase the workload on physicians and medical staff, as well as the risk of infection. However, the potential benefits were determined to outweigh the potential harms since both measurements enable the assessment of oxygen transport capacity in tissues.
CQ7-9: Noradrenaline or dopamine: Which should be used as a first-line vasopressor to treat patients with septic shock that are unresponsive to initial fluid resuscitation?
Answer (recommendation)
We recommend the use of noradrenaline as a first-line vasopressor to treat patients with septic shock that is unresponsive to initial resuscitation (1B) (rate of agreement, 100%).
Rationale
The systematic review reported by Avni et al. [147] was adopted as evidence as it had the highest quality. A total of 14 RCTs comparing noradrenaline and dopamine were identified, but these studies did not examine the time required to recover from septic shock. Noradrenaline administration significantly improved the 28-day mortality rate in comparison to dopamine (risk ratio, 0.89 [95% CI 0.81–0.98]). Regarding the ICU length of stay, the MD was 1.01 (95% CI − 0.65–2.66) as a result of the comparison between noradrenaline and other vasopressors, and no significant differences were observed. Regarding the incidence of complications, noradrenaline use resulted in a significantly lower incidence of complications compared to dopamine (risk ratio, 0.34 [95% CI 0.14–0.84]).
Regarding the benefit-risk balance, noradrenaline use resulted in a significant improvement in 28-day mortality rate in comparison to dopamine, and the frequency of harmful complications (fatal arrhythmias, myocardial/cerebral/upper, or lower limb ischemia/infarction, etc.) was significantly lower. Therefore, it was concluded that the potential benefits of noradrenaline use to treat patients with septic shock clearly outweighed the potential harms.
CQ7-10: Should adrenaline be used in septic shock when noradrenaline fails to improve the blood pressure?
Answer (opinion)
We suggest that adrenaline is used in cases in which the maintenance of hemodynamic status is insufficient despite appropriate fluid resuscitation and noradrenaline administration (expert consensus/no evidence) (rate of agreement, 100%).
Rationale
A literature search yielded 365 reports evaluating the effects of adrenaline in septic shock when noradrenaline fails to achieve a target blood pressure, and of these, eight were identified through the primary screening. No RCTs conforming to the PICO process for this CQ were found.
Regarding the benefit-risk balance, no RCT was examined for this CQ. Adrenaline as a first-line vasopressor has not shown significant improvements in mortality rates in comparison with noradrenaline. However, 20–40% of cases of septic shock are associated with SIMD which predicts worse outcomes [148], and it has been suggested that the administration of adrenaline may improve cardiac function in cases complicated by SIMD [149]. Although adrenaline use is associated with side effects such as tachycardia, decreased tissue perfusion, and lactate acidosis, no study has shown worse outcomes following adrenaline administration. It was concluded that the potential benefits of adrenaline use when noradrenaline fails to achieve target blood pressure clearly outweighed the potential harms.
CQ7-11: Should vasopressin be used in patients with septic shock who fail to achieve target blood pressure despite the use of noradrenaline?
Answer (opinion)
We suggest that vasopressin is used in patients with septic shock who show evidence of persistent hypotension despite adequate fluid resuscitation and the use of noradrenaline (expert consensus/quality of evidence “B”) (rate of agreement, 100%).
Rationale
A literature search yielded 365 records, and two RCTs [150, 151] were extracted for the meta-analysis after primary and secondary screening. ICU length of stay, 28-day mortality rate, and complication rate were assessed in these two RCTs, but time to shock reversal was not assessed. The risk ratios for 28-day mortality rate and complication rate were 0.90 (95% CI 0.76–1.07) and 0.73 (95% CI 0.24–2.23), respectively. The MD in ICU length of stay was − 0.95 days (95% CI − 1.73 to − 0.17).
In the two RCTs [150, 151], noradrenaline or noradrenaline plus vasopressin was administered when vasopressors were required to maintain target blood pressure despite adequate fluid resuscitation. Compared to using noradrenaline alone, the evidence of this systematic review and meta-analysis showed that adding vasopressin decreased the ICU length of stay by 1 day, but no difference was observed regarding 28-day mortality rate. In addition, no difference was observed in complication rate between the two groups. Based on these findings, it was concluded that the benefits of adding vasopressin when using noradrenaline alone fails to achieve target blood pressure likely outweigh the harms of adding it.
CQ7-12: Should dobutamine be used in patients with septic shock who show evidence of cardiac dysfunction?
Answer (opinion)
We suggest that dobutamine is used in septic shock when cardiac function remains diminished, and maintenance of hemodynamics is insufficient despite adequate fluid resuscitation and noradrenaline administration (expert consensus/quality of evidence “C”) (rate of agreement, 94.7%).
Rationale
Two RCTs [122, 123] were identified involving patients with septic shock in whom blood pressure could not be maintained with adequate fluid resuscitation and noradrenaline administration and cardiac function was normal or decreased. Adrenaline was administered to the control group. The risk ratio with respect to 28-day mortality rate was 0.88 (95% CI 0.69–1.13), and the incidence rate of complications was 0.87 (95% CI 0.62–1.22). The MD for the time to shock reversal and ICU length of stay were −1.00 day (95% CI − 1.89 to − 0.11) and 1.00 day (95% CI 0.33–1.67), respectively.
Regarding the benefit-risk balance, although the superiority of dobutamine versus adrenaline is not recognized, the 28-day mortality rate remained at approximately 40% in the RCT including patients predicted to have a very high risk of death, and as such, there appears to be some benefit in administering dobutamine. There were also no differences observed regarding the frequency of complications such as arrhythmia in comparison to the patients that received adrenaline. Based on the above observations, it was determined that the benefits of administering dobutamine likely outweigh the potential harms.