Adjunctive dobutamine in patients with septic cardiomyopathy and tissue hypoperfusion: a blinded randomised controlled multicentre trial study protocol of the ADAPT-dobutamine trial

Abstract

Introduction

Sepsis-induced left ventricular (LV) dysfunction participates in cardiovascular dysfunction and associated organ failure in patients with septic shock. The tested hypothesis is that dobutamine will reduce tissue hypoperfusion and secondary organ dysfunction in increasing oxygen delivery in fluid-filled patients with septic shock and associated symptomatic septic cardiomyopathy with documented low-flow state.

Methods and analysis

ADAPT–Dobutamine is a blinded, two parallel group, add-on, multicentre, randomised 1:1 and placebo-controlled trial. Patients will be included if hospitalised in the intensive care unit with septic shock (Sepsis-3 definition) and septic cardiomyopathy, identified using echocardiography (LV ejection fraction ≤40% and LV outflow tract velocity–time integral <14±1.5 cm). Non-inclusion criteria will include ventricular rate >130 bpm, severe ventricular arrhythmia, obstructive cardiomyopathy, severe aortic stenosis, ongoing acute coronary syndrome and indication for extracorporeal life support. Primary outcome will be the evolution of a modified Sequential Organ Failure Assessment score (excluding the neurologic system) during the initial intensive care unit stay encompassing screening (before randomisation), and from Day 1 to 3 after randomisation. Randomisation will be stratified on participating centres and previously documented heart failure (ejection fraction ≤40%). The use of open-labelled Dobutamine as a rescue therapy will be allowed in refractory shock based on strict clinical requirements. The use of alternative inotropes will not be allowed.

Ethics and dissemination

Approved by the Comité de Protection des Personnes Nord-Ouest IV from Lille (France) on 19 December 2019 (approval reference #19.04.05.36321). The results will be published in a peer-reviewed journal and presented in various congresses.

Trial registration number

NCT04166331.

Correspondence to Professor Philippe Vignon; [email protected]

STRENGTHS AND LIMITATIONS OF THIS STUDY

• Randomised controlled double-blind trial using a predictive enrichment strategy to increase the likelihood of a positive response to the chosen intervention in septic shock patients (Sepsis-3 definition).

• Echocardiography criteria of sepsis-induced left ventricular (LV) systolic dysfunction was previously validated in a large cohort of septic shock patients and was easy to obtain to allow the generalisability of patients screening for eligibility to the intervention.

• Required objective criterion of low flow associated with LV systolic dysfunction reinforces the relevance of tested therapeutic intervention.

• The intervention will involve potentially in only 15%–20% of patients with septic shock.

• Although relevant when compared with a two-point assessment, the evolution of a modified daily Sequential Organ Failure Assessment score during the first 3 days of evolution exposes to the risk of missing data.

Introduction

Background and rationale

Sepsis remains a leading cause of mortality worldwide.¹ Sepsis is currently defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection.² Septic shock corresponds to its most severe presentation, in which vasopressor support is required to maintain adequate blood pressure despite the correction of hypovolemia and tissue dysoxia is present, as reflected by a lactate level greater than 2 mmol/L.² Sepsis combines various and intricate alterations of vascular function, systolic and diastolic function of both ventricles and of the microvasculature.³ The loss of normal vascular tone, depressed cardiac function and compromised oxygen extraction result in tissue dysoxia and associated organ dysfunction.⁴ Functional consequences of sepsis-induced alteration of cardiac properties are usually attributed to the so-called ‘septic cardiomyopathy’, which currently lacks consensual definition.⁵ Left ventricular (LV) systolic dysfunction is the most frequent haemodynamic disturbance ascribed to septic cardiomyopathy.^6–8

Echocardiography is considered the modality of choice for the initial assessment of haemodynamically unstable patients with shock, especially of septic origin.^9–12 Sepsis-induced LV systolic dysfunction is observed in 18% of ventilated patients assessed on intensive care unit (ICU) admission for septic shock using transoesophageal echocardiography.¹³ When initially absent, septic cardiomyopathy may develop up to 72 hours after the initiation of vasopressors.^14–16 Sepsis-induced organ failures are interdependent.⁴ This interdependence is especially evident in the presence of sepsis-induced cardiovascular failure, which reduces systemic blood flow, thus exacerbating tissue hypoxia, mitochondrial dysfunction and ultimately resulting in further metabolic dysfunction of tissues with lactate production. In causing organ dysfunction, sepsis-induced cardiovascular failure is life-threatening, at least in the initial phase of the disease.⁴ Accordingly, the cardiovascular dysfunction assessed using the Sequential Organ Failure Assessment (SOFA) score¹⁷ recorded on ICU admission is strongly associated with mortality in patients with sepsis.¹⁸ In addition, patients with sepsis-induced LV systolic dysfunction, despite adequate fluid resuscitation, exhibit reduced cardiac index and LV ejection fraction, have higher lactate levels and require higher doses of norepinephrine.^{14 19 20}

In this specific subset of patients, optimisation of therapeutic management of septic cardiomyopathy may contribute to improving tissue perfusion in increasing oxygen delivery, and in turn may help reduce related organ dysfunctions.^{4 5} Dobutamine is the first-choice inotropic agent used in patients with low flow states as a result of myocardial depression.¹⁰ It increases cardiac index, stroke index and oxygen transport, without global effect on mean arterial pressure.²¹ These haemodynamic changes are dose-dependent and associated with a decrease in lactate level.²² In patients with sepsis-induced LV systolic dysfunction identified with echocardiography, Dobutamine efficiently increases cardiac output and LV ejection fraction.^{14 15} These beneficial effects are more marked in the subset of patients with the worst LV systolic dysfunction.²³ In septic shock patients with cardiac dysfunction and persistent hypoperfusion, despite adequate volume status and stabilised mean arterial pressure, additional use of Dobutamine is suggested by current Surviving Sepsis Campaign guidelines (weak recommendation, low quality evidence).²⁴ Levosimendan is a calcium sensitiser with inotropic and vasodilator effects, which has been proposed as an alternative inotropic support to Dobutamine in selected patients. In a recent large multicentre randomised controlled trial performed in septic patients, the addition of Levosimendan to standard treatment was not associated with less severe organ dysfunction or lower mortality, but with a higher risk of supraventricular tachyarrhythmia.²⁵ Current guidelines suggest not using Levosimendan in septic shock patients with cardiac dysfunction and tissue hypoperfusion despite stabilised haemodynamics (weak recommendation against, low quality evidence).²⁴

We hypothesised that Dobutamine will reduce tissue hypoperfusion and secondary organ dysfunction in increasing oxygen delivery in fluid-filled patients with septic shock under vasopressor support and associated symptomatic septic cardiomyopathy with documented low flow state.

Objectives

The primary objective of the trial is to assess the effects of adjunctive Dobutamine infusion when compared with placebo on organ failure during the first 3 days after randomisation in septic shock patients who received adequate fluid resuscitation and have stabilised mean blood pressure under vasopressor support and with symptomatic septic cardiomyopathy depicted by echocardiography.

Secondary objectives include the assessment of the effect of Dobutamine infusion on the evolution of indices of tissue hypoperfusion and haemodynamics during the first 3 days following randomisation, the need for organ support during ICU stay, the occurrence of severe cardiovascular adverse events during ICU stay, all-cause mortality, ICU and hospital lengths of stay, and the evolution of echocardiography parameters between screening (prior to randomisation) and Day 1 under a stabilised dose of experimental treatment.

When the information is available, we will assess: (i) the potential relation between cytokine levels (TNF-α, Interferon ɣ, Interleukin-6, 8 and 10) and haemodynamic profile at baseline and according to the haemodynamic response to study drug administration; (ii) the effect of the study drug on longitudinal myocardial fibres using speckle tracking; and (iii) the haemodynamic effects of the study drug when evaluated jointly by echocardiography and transpulmonary thermodilution.

Methods and analysis

Patient and public involvement

None.

Trial design and setting

ADAPT-Dobutamine is a blinded, two parallel group, add-on, multicentre, randomised, placebo-controlled trial (figure 1). The study will be conducted in 23 ICUs in France, including teaching and non-teaching hospitals listed in the online supplemental table.

Figure 1. Trial study design. *: the calculation of Sequential Organ Failure Assessment (SOFA) score is required for the diagnosis of septic shock using Sepsis-3 definition. Its value will be used as a reference for the evolution of the SOFA score during the first 3 days following randomisation (primary criterion). ICU, intensive care unit.

Eligibility criteria

Patients will be eligible to participate in the study if they fulfil all inclusion criteria, as follows:

• Age ≥18 years

• Hospitalised in ICU

• With septic shock on ICU admission or during ICU stay, according to the sepsis-3 definition² :

  • Clinically suspected or documented infection

  • Responsible for organ dysfunction: change in SOFA ≥2 points

  • With persisting hypotension (systolic and/or mean arterial pressure <90 mm Hg / < 65 mm Hg) despite adequate fluid resuscitation (≥ 30 mL/kg, unless presence of pulmonary venous congestion)

  • Requiring vasopressor support (Norepinephrine) to maintain a stable mean arterial pressure ≥65 mm Hg²⁴

  • Blood lactate >2 mmol/L within the 24 hours preceding randomisation

• Septic cardiomyopathy: echocardiographically measured or visually assessed LV ejection fraction ≤40% using the monoplane modified Simpson’s method²⁶ and LV outflow tract velocity-time integral <14±1.5* cm not related to persisting hypovolemia¹³ (*: integrates purposely a ‘low’ reproducibility of measurement of 10%)

• Signed informed consent: Patient but also relatives or emergency procedure by investigator with notification in the medical file informed consents will be available.

Patients with at least one of the following exclusion criteria will not be included. Echocardiography performed during screening to identify eligible patients will allow identifying some of these exclusion criteria (*):

• Pregnancy or breast feeding

• Hypersensitivity to Dobutamine, 5% Dextrose, or to the excipients

• Ventricular rate >130 bpm if non-sinus rhythm or >150 bpm if sinus rhythm

• Severe ventricular arrhythmia

• Obstructive cardiomyopathy* with a pressure gradient at rest ≥50 mm Hg,²⁷ unrelated to persisting hypovolemia²⁸

• Severe aortic stenosis*: mean gradient >40 mm Hg, peak aortic jet velocity >4 m/s, aortic valve area <1 cm² (aortic valve area index <0.6 cm²/m²)²⁹

• Ongoing acute coronary syndrome

• Indication for or insertion of any extracorporeal life support

• Decision to limit care or moribund status with a life expectancy <24 hour unrelated to the severity of underlying septic cardiomyopathy

• Absence of affiliation to social security

• Subject under juridical protection.

Due to the severity of septic shock in patients with frequently obtunded consciousness (septic encephalopathy or sedation in ventilated patients), signed informed consent will be obtained from the legal representative or from the next-of-keen if available. If unreachable or unable to present on due time, an emergency procedure will be available and used preferably after oral acceptance of the patient’s representative. In this case, signed informed consent to continue his/her participation in the study will be obtained from the patient as soon as possible. All information will be traced in the medical chart.

Intervention and comparator

Dobutamine is the reference inotrope, which is continuously administered intravenously in patients with systolic heart failure. It is fully transparent and non-foaming when diluted with 5% Dextrose. Placebo will be 5% Dextrose in the control arm to allow comparison with the intervention (Dobutamine) arm.

Both Dobutamine and the placebo will be administered intravenously using syringe pumps on a dedicated (central) venous line. Syringes will be changed at most every 24 hours as per good practice. No sodium bicarbonate or any alkaline solution will be added since they induce a loss of drug efficacy.

Adaptation of the dose of the experimental treatment will be standardised according to therapeutic targets, which will be left at the discretion of the attending physician. Lactate clearance could be used over a 6-hour time lag to titrate inotrope support as previously proposed,^{30 31} but not exclusively. Inotropes will be titrated based on repeated measurements of cardiac output,³¹ irrespective of the method used (eg, echocardiography and transpulmonary thermodilution)¹⁹ and according to local standard of care.

The experimental treatment will be initiated at a dose of 2.5 µg/kg/min,^32–34 and subsequently titrated using incremental steps of 2.5 µg/kg/min,^{21 23 35 36} up to a maximal dose of 10 µg/kg/min, according to both efficacy and cardiovascular tolerance. Both the duration of each step and optimal dose will be left at the judgement of the attending physician. Tapering and weaning of experimental treatment will not follow a predefined standardised algorithm. Neither the duration of experimental treatment nor the order of weaning with regard to vasopressor support will be standardised. Since the importance of de-escalation of vasoactive agents is comparable to the indication for initiation,¹⁰ particular attention will be paid not to prolong the experimental treatment infusion unnecessarily since it increases myocardial oxygen demand.²¹

During the administration of experimental treatment, continuous monitoring of cardiovascular parameters will be performed, including heart rate and rhythm, invasive blood pressure and vital parameters (eg, SpO₂, respiratory rate, urine output and level of consciousness). In the presence of a severe cardiovascular adverse event (eg, hypotension or decrease of mean blood pressure >10 mm Hg shortly after the initiation or stepwise increase of the study medication attributed to worsened vasoplegia, excessive sinus tachycardia >160 bpm or supraventricular arrhythmia >140 bpm, severe ventricular arrhythmia, new-onset acute coronary syndrome, ischaemic or haemorrhagic stroke), the infusion of experimental treatment will be transiently interrupted (half-life <3 min) until the event has resolved and will potentially be resumed to the step below than that at the time of interruption, at the discretion of the attending physician.

The use of open-labelled Dobutamine as a rescue therapy will be allowed in refractory shock based on strict clinical requirements including the presence of documented severe low flow state (ie, cardiac index <2.2 L/min/m²) despite high dose of Norepinephrine (> 2 µg/kg/min), associated with multiorgan failure, persisting high lactate level (> 4 mmol/L) and low ScvO₂ (< 60%) at least 2 hours after the started experimental treatment administered at its maximal dose,³⁷ without breaking blinding. In all cases, the medical reasons justifying the use of open-labelled Dobutamine will be detailed in the medical chart. Open-labelled Dobutamine administration will then be conducted using the same administration scheme, and the dose will be similarly adapted according to both the efficacy and haemodynamic tolerance, up to a maximal dose of 10 µg/kg/min than the experimental treatment. Accordingly, a patient belonging to the Dobutamine arm could potentially receive a maximal cumulated dose of 20 µg/kg/min, which has been commonly used.³⁵ In the presence of adverse cardiovascular effects of Dobutamine, the open-labelled drug will first be interrupted before withholding the infusion of experimental treatment if adverse effects persist. Open-labelled Dobutamine will first be weaned before the experimental treatment.

Outcomes

The primary outcome will be the evolution of a modified SOFA score excluding the gradation of the neurologic system during the initial ICU stay encompassing screening (before randomisation), and on Day 1, Day 2 and Day 3 after randomisation. This will allow us to assess the effects of adjunctive Dobutamine when compared with placebo on organ failures during the first 3 days after randomisation since SOFA score is an objective outcome which is reproducible and widely used worldwide, with high external validity.¹⁷ It allows serial (daily) gradation of six distinct organ functions from 0 (normal function) to 4 (worst dysfunction)¹⁷ and is a good predictor of in-hospital mortality.³⁸ Since the sole subjective assessment is that of the Glasgow Coma Scale, the neurologic component of the SOFA score will not be used in the present trial (modified SOFA score), as frequently omitted in trials enrolling patients with septic shock.²⁵

Secondary outcomes will be, with respect to corresponding secondary objectives:

• Biological indices of tissue dysoxia at screening (before randomisation), 6 hour after initiating the experimental treatment, and on Day 1, Day 2, and Day 3:

  • Circulating lactate level as a marker of tissue hypoperfusion^{30 37 39}

  • Central venous oxygen saturation (ScvO₂) as a marker of tissue oxygen extraction³⁰

• Haemodynamic status at screening (before randomisation), 6 hour after initiating the experimental treatment, and on Day 1, Day 2, and Day 3:

  • Arterial pressure, heart rate

  • Central venous pressure

  • Cardiac index and stroke volume measured using echocardiography⁴⁰ or using calibrated monitoring systems (eg, transpulmonary thermodilution)⁴¹

• Requirement of organ function supports during ICU stay:

  • Maximal dose and duration of vasopressor support

  • Maximal dose and duration of open-labelled Dobutamine used as rescue therapy

  • Duration of invasive mechanical ventilation

  • Requirement and number of sessions or duration of renal replacement therapy (excluding haemodialysis patients for chronic renal failure at randomisation)

• Number of days free from vasopressor support, invasive mechanical ventilation, renal replacement therapy during ICU stay

• Severe cardiovascular adverse events during ICU stay:

  • Hypotension related to worsened vasoplegia

  • Excessive sinus tachycardia >160 bpm or supraventricular arrhythmias with ventricular rate >140 bpm

  • Ventricular arrhythmias

  • New-onset acute coronary syndrome

  • Stroke (ischaemic or haemorrhagic)

• Day-7, ICU, Day-28 and Day-90 all-cause mortality

• Length of ICU and hospital stay

• Echocardiography, and if available transpulmonary thermodilution findings, at screening (before randomisation) and on Day 1 (during steady dose of experimental treatment): LV ejection fraction using the monoplane Simpson method,²⁶ velocity–time integral of LV outflow tract Doppler (stroke volume), E and A mitral Doppler maximal velocity, systolic (S’) and early diastolic maximal tissue Doppler velocity of mitral ring (E’), S’ measured at the lateral aspect of tricuspid ring and M-mode measurement of tricuspid annular plane systolic excursion (TAPSE), systolic pulmonary artery pressure, ratio of end-diastolic RV/LV areas in the long-axis view of the heart⁴²

• Cytokines level at 6 hour after randomisation.

Data collection methods

Parameters collected at inclusion

Inclusion visit will include:

• Patient’s characteristics: gender, age, height, weight, medical history, usual medications, suspected source of infection, body temperature; hospital and ICU date and time of admission, and location before ICU admission

• Circulatory and respiratory parameters: arterial pressure, heart rate, central venous pressure, cardiac index and stroke volume, diuresis; FiO₂, plateau pressure, total end-expiratory pressure, tidal volume, and respiratory rate

• Biology: arterial and central venous blood gases, lactates, blood cells count with leucocytes subtypes, haemoglobin, creatinine, bilirubin, AST, ALT, INR, hs-troponin (if available)

• Treatment of septic shock: total fluid volume resuscitation since hospital admission, vasopressor (type and dose) and date / time of initiation, date / time of first antibiotics administration, IV corticosteroids (dose, date / time of initiation), inhaled nitric oxide (date / time of initiation), invasive mechanical ventilation (date / time of initiation) and renal replacement therapy.

Parameters collected at H6

Postinitiation visit will be performed 6 hour after the initiation of experimental treatment and will record:

• Circulatory and respiratory parameters: arterial pressure, heart rate, central venous pressure, cardiac index and stroke volume, diuresis; FiO₂, plateau pressure, total end-expiratory pressure, tidal volume and respiratory rate

• Biology: arterial and central venous blood gases, lactates, blood cells count with leucocytes subtypes, haemoglobin, creatinine, bilirubin, AST, ALT, INR and hs-troponin (if available)

• Treatment of septic shock: total fluid volume resuscitation since the pre-inclusion visit, vasopressor (type and maximal dose), IV corticosteroids (maximal dose, date / time of initiation if not present on pre-inclusion visit), invasive mechanical ventilation (date / time of initiation if not present on previous visit), inhaled NO (date / time of initiation if not present on previous visit) and renal replacement therapy

• Maximal dose of the experimental treatment during the first 6 hour of administration

• Adverse and serious adverse events, especially severe cardiovascular adverse events (hypotension or decrease of mean blood pressure >10 mm Hg shortly after the initiation or stepwise increase of the study medication attributed to worsened vasoplegia, excessive sinus tachycardia >160 bpm or supraventricular arrhythmias with ventricular rate >140 bpm, severe ventricular arrhythmias, new-onset acute coronary syndrome, ischaemic or haemorrhagic stroke)

• Echocardiography (optional according to local standard of care): same parameters than at baseline, to assess both the efficacy and tolerance of therapy, according to standards of care. in participating centres

• Blood sample for cytokine analysis (Two 5 mL blood samples will be frozen (−80°C) for off-line cytokines level measurement.)

Parameters during follow-up visits

Follow-up visits will be performed on Day 1, Day 2, Day 3, Day 7, Day 28, at ICU discharge or on Day 28 whichever occurs first, and on Day 90.

Follow-up visits on Day 1, Day 2 and Day 3 will record:

• Modified SOFA score (primary outcome)

• Circulatory and respiratory parameters, as above-mentioned

• When patients will be haemodynamically monitored using echocardiography according to local standard of care, the examination performed on Day 2 and Day three will be recorded

• Biology, as above-mentioned (if available)

• Treatment of septic shock, as above-mentioned

• Experimental treatment since the previous visit: maximal dose, potential date / time of cessation

• Cumulated hydric balance since the previous visit

• Adverse and serious adverse events, as above-mentioned

• Echocardiography (optional according to local standard of care), as above-mentioned

Follow-up visits on Day 4, Day 5 and Day 6 will record:

• Circulatory and respiratory parameters, as above-mentioned

• Treatment of septic shock, as above-mentioned

• Experimental treatment, as above-mentioned

• Adverse and serious adverse events, as above-mentioned

• Echocardiography (optional according to local standard of care), as above-mentioned.

Follow-up visit on Day seven will record:

• Treatment of septic shock, as above-mentioned

• Experimental treatment, as above-mentioned

• Adverse and serious adverse events, as above-mentioned

• Biology, as above-mentioned

• Vital status

Follow-up visit at ICU discharge will record (or on Day 28 if occurs first):

• Treatment of septic shock, as above-mentioned

• Experimental treatment, as above-mentioned

• Adverse and serious adverse events, as above-mentioned

• Confirmation of diagnosis of septic shock and documentation of microorganisms, initial antibiotic therapy adapted or not.

• Vital status

Harms

Severe cardiovascular adverse events will be systematically screened during ICU stay, especially the following: hypotension related to worsened vasoplegia, excessive sinus tachycardia >160 bpm or supraventricular arrhythmias with ventricular rate >140 bpm, ventricular arrhythmias, new-onset acute coronary syndrome and stroke (ischaemic or haemorrhagic). In addition, on Day-7, in ICU, on Day-28 and Day-90 all-cause mortality will be recorded. Any other adverse events will be reported conventionally during ICU stay. Adverse events will be reported by investigators who will be blinded to the administered study drug and provided to the Data Safety Monitoring Board (DSMB).

Participant timeline

Since the treatment of septic shock should be undertaken as a medical emergency,¹ pre-inclusion visit to confirm the patient’s eligibility for enrolment in the trial and inclusion visit will typically occur on the same day. Patients may be screened again in the presence of a ‘secondary’ (delayed) septic cardiomyopathy developing during the first 3 days of ICU admission.^14–16 Parameters collected and successive visits during the study period are summarised in table 1.

Table 1

Description of the different steps from the inclusion visit to study end

	Screening (preinclusion) visit 1	Day 0 Baseline (inclusion) visit 2	H6 (postinitiation) visit 3	Day 1 Visit 4	Day 2 and Day 3 Visits 5 and 6	Day 7 Visit 7	ICU discharge* (± 2 days) Visit 8	Day 28 (±2 days) and Day 90 (± 6 days) Visits 9 and 10
Inclusion / exclusion criteria	✓
Pregnancy test (if applicable)	✓
Biology (local laboratory)†	✓	✓	✓	✓	✓	✓
ECG	✓
SOFA score(17)	✓			✓	✓
Echocardiography‡	✓			(✓)§
Informed consent	✓
Randomisation		✓
Patient’s characteristics¶		✓
Circulatory and respiratory parameters**		✓	✓	✓	✓
Treatment of septic shock††		✓	✓	✓	✓	✓	✓
Dobutamine / placebo administration			✓	✓	✓	✓	✓
Adverse and serious adverse events‡‡			✓	✓	✓	✓	✓
Cumulated hydric balance§§				✓	✓	✓
Vital status						✓	✓	✓
Micro-organisms documentation							✓¶¶

*or Day 28 if occurs first

†Arterial and central venous blood gases, lactates, blood cells count with leucocytes subtypes, hemoglobin, creatinine, bilirubin, AST, ALT, INR, hs-troponin (if available, except on Day 7)

‡Left ventricular systolic and diastolic function, right ventricular systolic function, systolic pulmonary artery pressure (see text for details)

§If part of local standard of care (not mandatory)

¶Gender, age, height, weight, past medical history, usual medications, narrative medical context, suspected source of infection, body temperature, hospital and ICU date and time of admission, location before ICU admission

**Arterial pressure, heart rate, central venous pressure, cardiac index and stroke volume, diuresis; FiO2, plateau pressure, total end-expiratory pressure, tidal volume, respiratory rate

††Total fluid volume resuscitation, vasopressor (type and dose) and date / time of initiation / cessation, antibiotics adapted / not and date / time of first administration, IV corticosteroids (dose, date / time of initiation / cessation), inhaled NO, invasive mechanical ventilation, renal replacement therapy

‡‡Especially all severe cardiovascular adverse events (hypotension or decrease of mean blood pressure > 10 mm Hg shortly after the initiation or stepwise increase of the study medication attributed to worsened vasoplegia, supraventricular arrhythmias with ventricular rate > 140 bpm, severe ventricular arrhythmias, acute coronary syndrome, ischemic or hemorrhagic stroke)

§§Difference between fluid administered (intravenous fluid, blood products, enteral fluids) and fluid lost (urine output, ultrafiltration, drain losses, enteral losses) in the last 24h period (Day 2 and 3), or since the Dobutamine / placebo initiation (Day 1), or since the last assessment (Day 7).

¶¶initial antibiotic therapy adapted or not

ICU, intensive care unit; SOFA, Sequential Organ Failure Assessment.

Sample size

Considering a two-point difference in the SOFA score at Day 3 and a SD of 7.2,^{19 20} the required number of patients would be 547 (90% power). Primary outcome (ie, SOFA score) will be repeatedly measured with a maximum of four measurements per patient (screening before randomisation, Day 1, Day 2 and Day 3). Accordingly, each patient will contribute to more than one observation. Nevertheless, distinct measurements performed in a single patient will be correlated and cannot be considered as independent observations. Based on personal data, we hypothesised that the correlation between the two measurements made in a single patient is approximately 0.25.^{19 20} According to Vicker’s approach,⁴³ the total number of required patients can then be divided by 2.28 and thus be reduced to 240.

Some patients are expected to die before Day 3, a proportion reaching 12.5% in our experience.^{19 20} Although these early fatalities will be taken into account in the analysis (intention-to-treat principle), we expect to have missing SOFA measurements since those patients will only undergo one, two or three SOFA assessments rather than the four evaluations expected initially. Accordingly, we purposely increased the sample size of 12.5%, and therefore plan to finally include 270 patients in the trial.

Importantly, the calculation of the study sample size is highly dependent on the 7.2 SD value, which has been derived from previously conducted observational studies in which inclusion criteria were slightly different from those of the ADAPT trial (prior to the Sepsis-3 definition, no need for documented septic cardiomyopathy). Consequently, we plan to estimate the actual SD in our study population to recalculate the required sample size for higher accuracy. This estimation will be performed after the inclusion of the first 90 patients (one-third of the initially planned sample size) without any statistical comparison between the two groups.

Recruitment

Patients will be screened at ICU admission or at the time of septic shock diagnosis in the Emergency Department where they frequently present initially. Patients’ eligibility will be confirmed during the initial haemodynamic assessment using echocardiography recommended in septic shock patients to early guide treatment of associated cardiovascular failure.^9–12 Although no time window will be required, this initial haemodynamic assessment is typically performed within 6 to 12 hours of vasopressor administration.^14–16 In septic shock patients with initially preserved LV ejection fraction, sequential evaluation of haemodynamic status will be performed as currently advocated,^{8 9 11} up to 72 hours after the initiation of vasopressors. This will allow detecting ‘secondary’ septic cardiomyopathy (ie, occurring after Day 1), which has been described in approximately one-third of patients with septic cardiomyopathy.^14–16 Septic shock patients with exclusion criteria will be registered in a screen failure log.

The ADAPT-Dobutamine trial will involve French ICUs with experience in conducting emergency trials, especially in the field of sepsis, most of them belonging to the CRICS-TRIGGERSEP (Clinical Research in Intensive Care and Sepsis – Trial Group for Global Evaluation and Research in SEPsis) network.^44–47 In early-goal directed therapy trials using inotropic support as part of a standardised treatment algorithm, Dobutamine was administered in 15% to 25% of septic shock patients during the first 72 hours following ICU admission.^48–51 Accordingly, we can anticipate that the subset of septic shock patients which is targeted for eligibility to enrolment in the present trial represents approximately 20% of septic shock patients admitted to participating ICUs. This is in keeping with the enrolment anticipation of one patient every 2 months per investigation site.

Randomisation: sequence generation, allocation concealment mechanism, and implementation

A computer process will be used to generate allocation sequences in a 1:1 ratio. Randomisation will be stratified on participating centres and on a medical history of a proven underlying congestive heart failure defined as a documented prior LV ejection fraction ≤40%.

Participants will be randomised using Ennov Clinical, an online central randomisation procedure. To ensure allocation concealment, the randomisation procedure will not be possible until the participant has been recruited into the trial. Notably, all selection criteria must be collected and met.

An allocation sequence will be generated by a statistician of the biometrical unit of the CIC Inserm 1415, who is not involved in the recruitment or follow-up of the participants.

Blinding

The study will be performed in a blinded manner. The patient, the investigator and study centre staff will be blinded to study drug allocation. Based on the randomisation code, the study nurse will solely be unblinded to independently prepare the experimental treatment. The study nurse will neither be in charge of the patient nor work in the unit where the patient has been admitted. Orange-coloured 60-mL syringes will be specifically used for the administration of the experimental treatment to ascertain blinding since Dobutamine may exhibit a pink colour which increases with time due to an oxidation of the drug without loss of potency.

Treatment will be unblinded in case of suspected unexpected serious adverse event if the knowledge of the experimental treatment significantly alters the management of the complication. Importantly, a procedure of unblinding will not be required before using a rescue therapy with open-labelled Dobutamine. Results of unblinding will neither be communicated to investigators nor sponsor.

Data management

All the information required by the protocol will be recorded in electronic case report forms (eCRF) developed using the Ennov Clinical software. Explanation must be provided for any missing data. Investigators will be uniformly trained to guarantee consistent data recordings and will be responsible for accurate data collection.

Data collection will be available during ICU stay, and vital status will be obtained in all patients at ICU and hospital discharge. Vital status, which is the only information required at Day 28 and Day 90 will be obtained by a phone call to the patient or his representative to reduce the risk of lost follow-up.

Statistical methods

Primary outcome

The analysis will consider all randomised patient (except those who will withdraw their consent and refuse their data to be used), and each patient will be considered in the group in which he/she has been allocated, whatever occurred. The primary outcome will be represented graphically by daily boxplots and will be analysed in the framework of a mixed model considering assessments realised at baseline, Day 1, 2 and 3.

Secondary outcomes

• Biological outcomes – which will be assessed at screening (before randomisation), H6, Day 1, Day 2 and Day 3 – will be analysed using mixed models

• Haemodynamic parameters – which will be assessed at baseline, H6, Day 1, Day 2 and Day 3, and potentially until Day 6 if the experimental treatment is still administered – will be analysed using mixed models

• Organ function supports:

• Vasopressor support and open-labelled Dobutamine if applicable:

  • Proportion of patients requiring these drugs will be compared using the Fine and Gray approach⁵² for competing risks with death and ICU discharge as the competing risk

  • Maximal dose will be compared using a Wilcoxon rank-sum test

  • Duration of treatment will be compared using a Wilcoxon rank-sum test

• Duration of invasive mechanical ventilation will be analysed using the competing risk approach, with death as the competing risk

• Number of sessions of renal replacement therapy will be compared using a negative binomial model with time in ICU as an offset

• Vasopressor and ventilator-free days as well as the number of days without renal replacement therapy during ICU stay will be compared using a Wilcoxon rank-sum test

• Severe cardiovascular adverse events during ICU stay will be analysed using the competing risk approach, with death and ICU discharge as competing risks

• Day-7, Day-28 and Day-90 all-cause mortality will be compared using chi-square tests. ICU mortality will be analysed using a competing-risk model with ICU discharge as a competing event with death during the ICU stay

• Lengths of ICU and hospital stay will be compared between the two groups using a competing risk approach (Fine and Grey’s model) with death considered as a competing event to end of stay

• Echocardiographic parameters will be compared between baseline and Day 1 (when available):

• Values will be compared within each group using paired t-tests

• Between group comparison will be performed considering crude differences between Day 0 and Day one and comparing them using Student t-tests or Wilcoxon rank-sum tests.

• Cytokine levels will be compared between groups using Student t-tests or Wilcoxon rank-sum tests.

A subgroup analysis in patients with proven congestive heart failure (LV ejection fraction ≤40%) at the time of the stratified randomisation will be performed using the same methods as the primary outcome and adding both a variable defining the subgroup and an interaction term between the treatment group and this latter variable.

Patients who withdraw consent before receiving the experimental treatment will be excluded from analysis and replaced to reach the required sample size. Patients who have an interruption of the experimental treatment irrespective of the reason (eg, withdraw of consent after initiation of study drug, unexpected serious adverse event potentially related to the experimental treatment) and patients who receive a rescue therapy will be analysed and kept in the group to which they have been allocated. Since information is collected during ICU stay, we anticipate very limited missing data on the primary outcome. Since the primary analysis is a mixed model for repeated data, we will not impute any data for missing observations. Finally, we expect few deaths during the early course of septic shock, and we do not plan to manage these situations differently than for missing data, considering that the impact on the result will be negligible.

Data monitoring committee

An independent (from investigation, pharmaceutical company and sponsor) DSMB will inform the sponsor on potential safety issues during the study and will make recommendations on trial continuation, final decision to continue or to stop being left at the entire discretion of the sponsor. The DSMB will independently and unblindly scrutinise especially severe cardiovascular adverse events potentially related to the experimental treatment.

The committee will be composed of five experts, one with expertise in statistics, three with expertise in intensive care medicine, and one Pharmacist with expertise in vigilance.

All members of the DSMB are selected on the basis of their expertise and absence of conflict of interest with the trial. One of them will be nominated as chair by the coordinating investigator. Frequency of meetings and managing rules using a charter will be given to the DSMB members before their acceptance in participating in the committee.

Trial monitoring

In the ADAPT trial, expected severe cardiovascular adverse events are of particular interest and will constitute a secondary outcome, as detailed above. The sponsor will report to the competent authority all relevant information on suspected unexpected serious reactions or events to the experimental treatment. The investigator will be responsible for collecting exhaustively all adverse events in the eCRF and evaluating its potential relationship with the experimental treatment.

Ethics and dissemination

Research ethics approval

The study protocol including the list of participating centres was approved by the Comité de Protection des Personnes (CPP) Nord-Ouest IV from Lille (France) on 19 December 2019 (approval reference #19.04.05.36321). Each hospital administration of participating centres will sign a dedicated convention.

Dissemination policy

The results will be published in a peer-reviewed journal of intensive care medicine and presented in scientific congresses related to the subject of the study.

Protocol amendments

Any substantial change, that is, any change that is likely to have a significant impact on the protection of persons, on the conditions of validity and on the results of the research, on the quality and safety of the products tested, on the interpretation of scientific documents that support the sequence of the research or the way in which the research is conducted, is subject to a written amendment submitted to the sponsor. The latter must obtain, prior to its implementation, a favorable opinion from the CPP, and, where applicable, authorisation from the reporting member state.

Consent or assent

Signed informed consent will be obtained by the investigator from the patient (online supplemental material), or if not able to consent from his legal representative, or from the next-of-kin if available. If unreachable or unable to present on due time, an emergency procedure will be available and used preferably after oral acceptance of patient’s representative. In this case, signed informed consent to continue his/her participation in the study will be obtained from the patient as soon as possible. The patient or his representative will receive a written information document describing the study.

Confidentiality

All information related to the study, including participant information will be stored securely in a dedicated locked files with limited access in each participating center. Data on the participants and administrative forms will be identified by a coded identification number. The sponsor will ensure that each participant has given his/her written agreement for access to the individual data concerning them and strictly necessary for the quality control of the research.

Ancillary and post-trial care

N/A.

Trial registration

ADAPT-Dobutamine study is registered in clinicaltrials.gov (NCT04166331).

Protocol and statistical analysis plan

The protocol including the statistical analysis plan has been published. The data collected for the study will be accessible to individuals authorised by Limoges university hospital for 2 years following the last publication of the research results.

Data sharing

The datasets used and/or analyzed during the current study will be available from the corresponding author on reasonable request.

We thank Tifenn Le Naour and Sandrine Naturel for their support and precious help in

the elaboration of the study protocol.

Ethics statements

Patient consent for publication

Not applicable.

Footnote

Contributors PV, BE and BG designed the study and drafted the manuscript. JL, JV and MG participated in manuscript drafting. All authors approved the submitted version of the manuscript. PV is the guarantor.

Funding French Hospital Program of Clinical Research (Programme Hospitalier de Recherche Clinique National) 2018.

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

References

¹ Cecconi M, Evans L, Levy M, et al. Sepsis and septic shock. Lancet 2018; 392: 75–87. doi:10.1016/S0140-6736(18)30696-2

² Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315: 801–10. doi:10.1001/jama.2016.0287

³ Hochstadt A, Meroz Y, Landesberg G. Myocardial dysfunction in severe sepsis and septic shock: more questions than answers? J Cardiothorac Vasc Anesth 2011; 25: 526–35. doi:10.1053/j.jvca.2010.11.026

⁴ Abraham E, Singer M. Mechanisms of sepsis-induced organ dysfunction. Crit Care Med 2007; 35: 2408–16. doi:10.1097/01.ccm.0000282072.56245.91

⁵ Beesley SJ, Weber G, Sarge T, et al. Septic Cardiomyopathy. Crit Care Med 2018; 46: 625–34. doi:10.1097/CCM.0000000000002851

⁶ Vieillard-Baron A, Cecconi M. Understanding cardiac failure in sepsis. Intensive Care Med 2014; 40: 1560–3. doi:10.1007/s00134-014-3367-8

⁷ Aneman A, Vieillard-Baron A. Cardiac dysfunction in sepsis. Intensive Care Med 2016; 42: 2073–6. doi:10.1007/s00134-016-4503-4

⁸ Vignon P. Continuous cardiac output assessment or serial echocardiography during septic shock resuscitation? Ann Transl Med 2020; 8: 797. doi:10.21037/atm.2020.04.11

⁹ Cecconi M, De Backer D, Antonelli M, et al. Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine. Intensive Care Med 2014; 40: 1795–815. doi:10.1007/s00134-014-3525-z

¹⁰ Vincent J-L, De Backer D. Circulatory Shock. N Engl J Med 2013; 369: 1726–34. doi:10.1056/NEJMra1208943

¹¹ Seymour CW, Rosengart MR. Septic Shock: Advances in Diagnosis and Treatment. JAMA 2015; 314: 708–17. doi:10.1001/jama.2015.7885

¹² Labovitz AJ, Noble VE, Bierig M, et al. Focused cardiac ultrasound in the emergent setting: a consensus statement of the American Society of Echocardiography and American College of Emergency Physicians. J Am Soc Echocardiogr 2010; 23: 1225–30. doi:10.1016/j.echo.2010.10.005

¹³ Geri G, Vignon P, Aubry A, et al. Cardiovascular clusters in septic shock combining clinical and echocardiographic parameters: a post hoc analysis. Intensive Care Med 2019; 45: 657–67. doi:10.1007/s00134-019-05596-z

¹⁴ Vieillard-Baron A, Caille V, Charron C, et al. Actual incidence of global left ventricular hypokinesia in adult septic shock. Crit Care Med 2008; 36: 1701–6. doi:10.1097/CCM.0b013e318174db05

¹⁵ Bouferrache K, Amiel J-B, Chimot L, et al. Initial resuscitation guided by the Surviving Sepsis Campaign recommendations and early echocardiographic assessment of hemodynamics in intensive care unit septic patients: a pilot study. Crit Care Med 2012; 40: 2821–7. doi:10.1097/CCM.0b013e31825bc565

¹⁶ Boissier F, Razazi K, Seemann A, et al. Left ventricular systolic dysfunction during septic shock: the role of loading conditions. Intensive Care Med 2017; 43: 633–42. doi:10.1007/s00134-017-4698-z

¹⁷ Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996; 22: 707–10. doi:10.1007/BF01709751

¹⁸ Blanco J, Muriel-Bombín A, Sagredo V, et al. Incidence, organ dysfunction and mortality in severe sepsis: a Spanish multicentre study. Crit Care 2008; 12: R158. doi:10.1186/cc7157

¹⁹ Vignon P, Begot E, Mari A, et al. Hemodynamic Assessment of Patients With Septic Shock Using Transpulmonary Thermodilution and Critical Care Echocardiography: A Comparative Study. Chest 2018; 153: 55–64. doi:10.1016/j.chest.2017.08.022

²⁰ Vignon P, Repessé X, Bégot E, et al. Comparison of Echocardiographic Indices Used to Predict Fluid Responsiveness in Ventilated Patients. Am J Respir Crit Care Med 2017; 195: 1022–32. doi:10.1164/rccm.201604-0844OC

²¹ Vincent JL, Roman A, Kahn RJ. Dobutamine administration in septic shock: addition to a standard protocol. Crit Care Med 1990; 18: 689–93. doi:10.1097/00003246-199007000-00001

²² Gutierrez G, Clark C, Brown SD, et al. Effect of dobutamine on oxygen consumption and gastric mucosal pH in septic patients. Am J Respir Crit Care Med 1994; 150: 324–9. doi:10.1164/ajrccm.150.2.8049810

²³ Enrico C, Kanoore Edul VS, Vazquez AR, et al. Systemic and microcirculatory effects of dobutamine in patients with septic shock. J Crit Care 2012; 27: 630–8. doi:10.1016/j.jcrc.2012.08.002

²⁴ Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med 2021; 47: 1181–247. doi:10.1007/s00134-021-06506-y

²⁵ Gordon AC, Perkins GD, Singer M, et al. Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis. N Engl J Med 2016; 375: 1638–48. doi:10.1056/NEJMoa1609409

²⁶ Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015; 28: 1–39. doi:10.1016/j.echo.2014.10.003

²⁷ Maron MS, Olivotto I, Zenovich AG, et al. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation 2006; 114: 2232–9. doi:10.1161/CIRCULATIONAHA.106.644682

²⁸ Chauvet J-L, El-Dash S, Delastre O, et al. Early dynamic left intraventricular obstruction is associated with hypovolemia and high mortality in septic shock patients. Crit Care 2015; 19: 262. doi:10.1186/s13054-015-0980-z

²⁹ Bonow RO, Leon MB, Doshi D, et al. Management strategies and future challenges for aortic valve disease. Lancet 2016; 387: 1312–23. doi:10.1016/S0140-6736(16)00586-9

³⁰ Jones AE, Shapiro NI, Trzeciak S, et al. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 2010; 303: 739–46. doi:10.1001/jama.2010.158

³¹ Annane D, Ouanes-Besbes L, de Backer D, et al. A global perspective on vasoactive agents in shock. Intensive Care Med 2018; 44: 833–46. doi:10.1007/s00134-018-5242-5

³² Vallet B, Chopin C, Curtis SE, et al. Prognostic value of the dobutamine test in patients with sepsis syndrome and normal lactate values: a prospective, multicenter study. Crit Care Med 1993; 21: 1868–75. doi:10.1097/00003246-199312000-00014

³³ Rhodes A, Lamb FJ, Malagon I, et al. A prospective study of the use of a dobutamine stress test to identify outcome in patients with sepsis, severe sepsis, or septic shock. Crit Care Med 1999; 27: 2361–6. doi:10.1097/00003246-199911000-00007

³⁴ Hayes MA, Timmins AC, Yau EH, et al. Oxygen transport patterns in patients with sepsis syndrome or septic shock: influence of treatment and relationship to outcome. Crit Care Med 1997; 25: 926–36. doi:10.1097/00003246-199706000-00007

³⁵ Jellema WT, Groeneveld ABJ, Wesseling KH, et al. Heterogeneity and prediction of hemodynamic responses to dobutamine in patients with septic shock. Crit Care Med 2006; 34: 2392–8. doi:10.1097/01.CCM.0000233871.52553.CD

³⁶ Kumar A, Schupp E, Bunnell E, et al. Cardiovascular response to dobutamine stress predicts outcome in severe sepsis and septic shock. Crit Care 2008; 12: R35. doi:10.1186/cc6814

³⁷ Jansen TC, van Bommel J, Schoonderbeek FJ, et al. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med 2010; 182: 752–61. doi:10.1164/rccm.200912-1918OC

³⁸ de Grooth H-J, Geenen IL, Girbes AR, et al. SOFA and mortality endpoints in randomized controlled trials: a systematic review and meta-regression analysis. Crit Care 2017; 21: 38. doi:10.1186/s13054-017-1609-1

³⁹ Annane D, Vignon P, Renault A, et al. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. Lancet 2007; 370: 676–84. doi:10.1016/S0140-6736(07)61344-0

⁴⁰ Gu W-J, Zhang Z, Bakker J. Early lactate clearance-guided therapy in patients with sepsis: a meta-analysis with trial sequential analysis of randomized controlled trials. Intensive Care Med 2015; 41: 1862–3. doi:10.1007/s00134-015-3955-2

⁴¹ Zoghbi WA, Quinones MA. Determination of cardiac output by Doppler echocardiography: a critical appraisal. Herz 1986; 11: 258–68.

⁴² Monnet X, Persichini R, Ktari M, et al. Precision of the transpulmonary thermodilution measurements. Crit Care 2011; 15: R204. doi:10.1186/cc10421

⁴³ Jardin F, Dubourg O, Bourdarias JP. Echocardiographic pattern of acute cor pulmonale. Chest 1997; 111: 209–17. doi:10.1378/chest.111.1.209

⁴⁴ Vickers AJ. How many repeated measures in repeated measures designs? Statistical issues for comparative trials. BMC Med Res Methodol 2003; 3: 22. doi:10.1186/1471-2288-3-22

⁴⁵ Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med 2018; 378: 809–18. doi:10.1056/NEJMoa1705716

⁴⁶ Reignier J, Boisramé-Helms J, Brisard L, et al. Enteral versus parenteral early nutrition in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2). The Lancet 2018; 391: 133–43. doi:10.1016/S0140-6736(17)32146-3

⁴⁷ François B, Chastre J, Eggiman P, et al. The SAATELLITE and EVADE Clinical Studies Within the COMBACTE Consortium: A Public-Private Collaborative Effort in Designing and Performing Clinical Trials for Novel Antibacterial Drugs to Prevent Nosocomial Pneumonia. Clin Infect Dis 2016; 63 Suppl 2: S46–51. doi:10.1093/cid/ciw245

⁴⁸ Francois B, Jeannet R, Daix T, et al. Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial. JCI Insight 2018; 3: e98960. doi:10.1172/jci.insight.98960

⁴⁹ Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 2015; 372: 1301–11. doi:10.1056/NEJMoa1500896

⁵⁰ ProCESS Investigators, Yealy DM, Kellum JA. A Randomized Trial of Protocol-Based Care for Early Septic Shock. N Engl J Med 2014; 370: 1683–93. doi:10.1056/NEJMoa1401602

⁵¹ The ARISE Investigators and the ANZICS Clinical Trials Group, Peake SL. Goal-Directed Resuscitation for Patients with Early Septic Shock. N Engl J Med 2014; 371: 1496–506. doi:10.1056/NEJMoa1404380

⁵² Fine JP, Gray RJ. A Proportional Hazards Model for the Subdistribution of a Competing Risk. J Am Stat Assoc 1999; 94: 496–509. doi:10.1080/01621459.1999.10474144