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• play_arrowINCEPTION Trial – ECMO CPR in Cardiac Arrest
  Dr Swapnil Pawar Blog written by Dr Jose Chacko

Early Extracorporeal CPR for Refractory Out-of-Hospital Cardiac Arrest

Suverein MM, Delnoij TSR, Lorusso R, et al. Early Extracorporeal CPR for Refractory Out-of-Hospital Cardiac Arrest. N Engl J Med. 2023 Jan 26;388(4):299-309

Background

In refractory cardiac arrest, the addition of extracorporeal membrane oxygenation to conventional cardiopulmonary life support (e-CPR) may help maintain organ perfusion and alleviate neurological damage. Besides, it offers an opportunity to identify the underlying cause and apply therapeutic interventions, including coronary revascularization.

Two previous randomized controlled trials (RCTs) have evaluated the efficacy of e-CPR in patients who suffered out-of-hospital cardiac arrest. The ARREST trial was stopped after enrolling 30 patients as early results favoured e-CPR. However, there were few survivors in either group (six in the e-CPR group and a lone survivor in the conventional group). The Prague e-CPR trial, including 256 patients, was terminated prematurely for futility, although a favourable 6-month survival was higher with e-CPR (31.5% vs. 22%). Against this background, the INCEPTION trial investigators conducted this trial to assess survival with a favourable neurological outcome with e-CPR compared to conventional CPR among patients who sustained out-of-hospital cardiac arrest with a ventricular arrhythmia as the initial rhythm.

Population/design

The INCEPTION trial was an RCT conducted between May 2017 and February 2021, including ten cardiosurgical centers served by 12 emergency medical services in the Netherlands. Adult patients 18–70 years old were eligible if they had sustained a witnessed, refractory, out-of-hospital cardiac arrest with ventricular fibrillation, ventricular tachycardia, or any other shockable initial rhythm. Refractory cardiac arrest was defined as failure to attain a return of spontaneous circulation (ROSC) within 15 minutes of arrest. Patients were randomized in a 1:1 ratio to e-CPR or conventional CPR.

Excluded

The trial excluded patients who attained ROSC within 15 minutes, those with terminal heart failure, severe COPD, disseminated malignancy, pregnancy, bilateral femoral bypass surgery, other known contraindications for e-CPR, or an expected duration of >60 minutes between cardiac arrest and cannulation. Patients with a poor neurological state at baseline were also excluded.

Inclusion criteria were reviewed after arrival at the hospital. Patients randomized to e-CPR but who took more than 60 minutes for cannulation were included. E-CPR was not performed If ROSC was achieved before initiation but was analyzed based on an intention-to-treat basis. Post-resuscitation care, including targeted temperature management and conduct of extracorporeal circulation, was based on institutional protocols according to current guidelines.

E-CPR group

Percutaneous or surgical cannulation of the femoral vein and the femoral artery was carried out. The e-CPR circuit was chosen based on local availability. A distal cannula for lower limb perfusion was encouraged but not mandatory. Chest compressions were carried out throughout this period with minimal interruption.

Post-resuscitation care

Targeted temperature management at 33–36 C for 24 hours was carried out in both groups. Normothermia was maintained for 72 hours. Mechanical ventilation was aimed to maintain normal PaO2 and PCO2 levels. The target mean arterial pressure was set at 65­–70 mm Hg. Coronary angiography was performed as appropriate. The decision to cease treatment was left to the clinician.

Sample size

The authors hypothesized an improvement in the 30-day survival with a favourable neurological outcome from 8 to 30% with e-CPR and calculated an initial sample size of 49 patients in each group. However, as several patients assigned to e-CPR achieved ROSC before cannulation, the sample size was revised to 134 patients, 67 in each group.

Results

A total of 160 patients underwent randomization; 26 were excluded – the reasons for exclusion were unwitnessed arrest, age >70 years old, initial unshockable rhythm, and attainment of ROSC in <15 min. In the primary analysis, 70 patients were included from the e-CPR group and 63 from the conventional group. The mean age was 54 vs. 57 years in the e-CPR vs. control groups; nearly 90% of subjects in both groups were male. Both groups were well matched at baseline regarding co-morbidities.

Other important baseline characteristics

| Characteristic | e-CPR (70 patients) | Conventional (63 patients) | | Witnessed arrest (no, %) | 68 (97) | 63 (98) | | CPR within 5 min (no, %) | 69 (99) | 61 (95) | | Arrest-ambulance time (min) | 8±4 | 8±4 | | Arrest-ER arrival (min) | 36±12 | 38±11 | | No of defibrillations | 8±5 | 9±6 |

In the e-CPR group, 18/70 patients did not receive the intervention as planned. Among these patients, a stable ROSC was achieved without e-CPR in 13, logistic failure occurred in three, while treatment was discontinued in three. In the remaining 62, cannulation and extracorporeal circulation was successful in 46 (88%) of patients. Three patients crossed over from the conventional to the e-CPR group. A stable ROSC was achieved in 18/70 (26%) in the e-CPR group and 20/64 (31%) in the conventional CPR group.

Important clinical outcomes

| Outcome | e-CPR (70 patients) | Conventional (63 patients) | OR (95% CI) | | Primary outcome: 30-d survival with CPC 1 or 2 (independent ADLs)(no, %) | 14 (20) | 10 (16) | 1.4 (0.5–3.5) | | 3-month survival with CPC 1 or 2 | 12 (18) | 9 (14) | 1.5 (0.6–3.8) | | 6-month survival with CPC 1 or 2 | 14 (20%) | 10 (16) | 1.3 (0.5–3.3) |

E-CPR was associated with higher survival to ICU admission. Survival to ICU and hospital discharge were similar between the two groups.

Adverse events per patient were similar in both groups. Discontinuation of treatment was carried out in 80% of patients in both groups. The reason for discontinuation was unfavourable neurological state, multiorgan failure, cannulation of ECLS failure, and non-availability of further treatment options.

Limitations

• In the e-CPR group, 18/70 (25.7%) patients did not receive the intervention as planned; among them, a stable ROSC was achieved in 13 patients. However, analysis was by intention to treat (these patients were included in the e-CPR group for analysis)
• Although the time to cannulation was set to 60 minutes, it was delayed in some patients; however, these patients were not excluded from the trial.
• Initiation of e-CPR was unsuccessful in 6 patients
• Three patients in the conventional group crossed over to e-CPR; again, analysis was by intention to treat. However, there were no survivors among these patients.
• One patient in each arm was lost to follow-up.
• Neurological assessment could be over the phone; this may have led to an incomplete assessment.
• Lack of blinding could have led to bias

Summary

The currently available evidence from three RCTs does not support the routine use of e-CPR in patients who suffer out-of-hospital cardiac arrest. It holds promise as an intervention for the future. However, the efficacy of e-CPR needs to be established in larger, more robust studies with adequate statistical power. Until then, this technique cannot be routinely recommended among patients who sustain out-of-hospital cardiac arrest.

The post INCEPTION Trial – ECMO CPR in Cardiac Arrest first appeared on Critical Care Education.

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• play_arrowCLOVERS Trial – Early restrictive vs liberal fluid resuscitation for Septic shock
  Dr Swapnil Pawar Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension

(The CLOVERS trial)

National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network; Shapiro NI, Douglas IS, Brower RG, et al. Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension. N Engl J Med. 2023 Jan 21. doi: 10.1056/NEJMoa2212663. Epub ahead of print. PMID: 36688507.

Blog written by Dr Jose Chacko

Background

Fluid resuscitation is one of the key early interventions in patients with septic shock. However, excessive fluid administration may result in fluid overload and organ dysfunction. An alternative strategy is a fluid-restrictive approach combined with the early use of vasopressors to maintain perfusion pressures. A restrictive strategy may reduce adverse effects associated with fluid overload an improve clinical outcomes. The CLASSIC pilot randomized clinical trial (2022) revealed no difference in 90-day mortality with a restrictive approach compared with unguided resuscitation.

Population and design

The study was conducted between March 7, 2018, to January 31, 2022, and enrolled 1563 patients at 60 centers in the US.

Eligibility

• Adult patients with suspected for confirmed infection and hypotension with a systolic blood pressure <100 mm Hg after ≥1000 ml of IV fluids.

Exclusion

• More than 4 h after meeting the eligibility criteria above
• More than 24 h after presentation to hospital
• Received >3000 ml fluid
• Fluid overload
• Severe hypovolemia not due to sepsis

Patients were randomized in a 1:1 ratio to a restrictive or a liberal strategy. A sample size of 2320 patients was to demonstrate a 4.5% difference in death before discharge (the primary outcome) in favor of the restrictive group (15% vs. 10.5%) for 90% power and two-sided alpha level of 0.05

Restrictive group

Boluses up to 2 L, including pre-randomization  norepinephrine, second vasopressor for MAP <65 or sys BP <90

Rescue fluid of 500 ml bolus if –

• Severe hypotension (SBP < 70, MAP < 50 mmHg)
• Refractory hypotension (SBP <90 or MAP <65 on Norepinephrine > 20 mcg min or equivalent)
• Lactate > 4 mmol/L and increasing after 2 hours of therapy
• Sinus HR > 130 for 15 mins
• Echocardiographic evidence or haemodynamic evidence of extreme hypovolaemia
• Felt to be in the best interests by treating the team

Liberal group

2 L at randomization (may restrict to 1 L)  additional 500 ml boluses if

• MAP < 65 or SBP < 90 mmHg
• Lactate > 4 mmol/L and increasing
• UOP < 30mls/hr
• HR > 110 bpm (sinus)
• Requirement for vasopressors
• Measured or clinical assessment

Rescue vasopressors if:

• severe hypotension (defined as per restrictive group),
• lactate > 4 mmol/L and increasing after 2 hours,

• 5L total IV fluid given,

• clinical manifestations of fluid overload or
• treating the team felt to be in the best interests

Results

The study was stopped for futility after the enrolment of 1563 patients. Patients were well-matched at baseline.

Fluids received, restrictive vs. liberal groups.

| Timeline | Restrictive (ml) | Liberal (ml) | | 6 h post-randomization | 500 (130–1097) | 2300 (2000–3000) | | 24 h post-randomization | 1267 (555–2279) | 3400 (2500–4495) | | 24 h including pre-enrolment | 3300 (2550–4350) | 5400 ml (4400–6575) |

• Vasopressors: 59% vs. 37%; initiated earlier, continued for longer in the restrictive group in the first 24 hours
• Ringer’s Lactate the most common fluid
• Peripheral administration of vasopressors was safe. Five hundred patients received peripherally administered vasopressors; there were three possible instances of extravasation, with no clinical consequences

Outcomes*

| Outcome | Restrictive (782) | Liberal (781) | | Death before discharge at 90 d | 14% | 14.9% | | Organ support-free at 28 d | 24 d | 23.6 d | | Ventilator-free at 28 d | 23.4 d | 22.8 d | | RRT-free at 28 d | 24.1 d | 23.9 d | | Vasopressor-free at 28 d | 22 d | 21.6 d | | ICU-free at 28 d | 22.8 d | 22.7 d | | Hospital-free at 28 d | 16.2 d | 15.4 d | | All-cause mortality 90 d (any location) | 22.4% | 21.9% |

*None of the outcomes were significantly different between groups

Limitations –

• Fluid administration of 1–3 liters was allowed before enrolment
• Vasopressors were already in use prior to randomization in both groups (restrictive vs. liberal: 21% vs. 18%)
• Protocol amendment: the initial bolus fluid could be restricted to 1 L if the patient was considered fluid replete
• The study was terminated early before attaining sample size
• Enrolment was left to physician judgment
• No specific strategy was employed for the assessment of volume responsiveness
• Some patients in the restrictive group received more fluids than according to protocol; those in the liberal group received early vasopressors
• The results may not apply to subgroups of patients with different co-morbidities
• The trial was unblinded trial with the potential for bias
• Both groups were protocol driven; there was no “usual” care group (this created a major controversy with citizens groups contending that the trial was purely experimental)
• Hemodynamic targets were the same for both groups
• The study was limited to 24 hours
• Patients were in the early phase of sepsis, who presented to the emergency department. The results may not apply to more severely ill patients and later in the course of illness

Summary –

It’s essential to have a vigilant approach to fluid resuscitation and use vasopressors cautiously if and when needed.

We recommend against a fixed dogmatic approach towards resuscitation in patients with septic shock.

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• play_arrowBOX Trial – Oxygenation targets in OHCA Comatose survivors
  Dr Swapnil Pawar Oxygen Targets in Comatose Survivors of Cardiac ArrestSchmidt H, Kjaergaard J, Hassager C, et al. Oxygen Targets in Comatose Survivors of Cardiac Arrest. N Engl J Med. 2022 Oct 20;387(16):1467-1476. doi: 10.1056/NEJMoa2208686. Epub 2022 Aug 27. PMID: 36027567.

Blog written by – Dr Jose Chacko

Background

Following successful resuscitation from cardiac arrest, reperfusion injury may exacerbate damage to the brain. The appropriate oxygenation target during mechanical ventilation in comatose survivors of out-of-hospital cardiac arrest is unknown. Findings from observational studies and animal models suggest worsening of brain injury with hyperoxia. In the ICU-ROX study, subgroup analysis suggested improved outcomes with lower oxygen targets in patients with hypoxic-ischemic encephalopathy. The Blood Pressure and Oxygenation Targets in Postresuscitation Care (BOX) trial was aimed to evaluate outcomes with a restrictive compared with a liberal oxygenation strategy among comatose survivors of out-of-hospital cardiac arrest.

Population and design

The study was conducted in two tertiary care centers in Denmark between March 2017 and December 2021. The study included patients who attained return of spontaneous circulation (ROSC) within 20 minutes and remained comatose after out-of-hospital cardiac arrest from a presumed cardiac cause. The study excluded patients who suffered cardiac arrest due to a presumed non-cardiac cause if >4 hours had elapsed from ROSC to screening and if the systolic BP remained <80 despite supportive treatment. The BOX trial was a 2-by-2 factorial study with oxygen and blood pressure targets. The study used block randomization, stratified by site.

Restrictive group

In the restrictive group, PaO2 of 68 to 75 mm Hg (9 to 10 kPa) was targeted.

Liberal

In the liberal group, the target PaO2 was 98 to 105 mm Hg (13 to 14 kPa)

Management in both groups

Patients in both groups were sedated and mechanically ventilated with temperature control to 36°C for at least 24 hours. After 24 hours, the core temperature was gradually allowed to rise, and sedation was weaned off. Arterial blood-gas analysis was performed at regular intervals for 120 hours (5 days) after randomization or until removal of the arterial catheter. The FiO2 was initially set at 0.3 in the restrictive and 0.6 in the liberal group and adjusted to the target PaO2 in each arm. The FiO2 was increased if the SaO2 dropped below 93%. Ventilation management was at the clinician’s discretion.

Sample size

The authors calculated a sample size of 732 patients to detect a 10% absolute difference in the primary outcome (death or severe disability at 90 d) with 80% power, assuming a mortality of 28% at a two-sided alpha level of 0.05. The study aimed to randomize 800 patients, with 400 in each group.

Results

On the intention to treat analysis, 789 patients were included; 394 were in the restrictive group and 395 in the liberal group. Baseline characteristics were well-matched between the two groups. Restrictive vs. liberal: shockable rhythm 85 vs. 84.5%; witnessed arrest: 84.5 vs. 86%; bystander CPR: 89.2 vs. 85.8%; time to ROSC: mean duration of 21 min in both groups. Patients in both groups had similar P/F ratios on admission to the ICU. Separation of oxygenation levels was evident within 2–4 hours and maintained for the first 48 hours. The median duration of ventilation was 57 vs. 61 hours.

Outcomes

| Outcome | Restrictive (394 patients) | Liberal (395 patients) | Treatment effect | | Primary outcome Death or severe disability (dependent for ADLs, coma, vegetative, brain dead) whichever occurred first at 90 d post-randomization | 126 (32.0%) | 134 (33.9%) | 0.95 (0.75–1.21) (not significant) | | Death at 90 d | 113 (28.7%) | 123 (31.1%) | 0.93 (0.72–1.20) (not significant) | | AKI requiring RRT | 34 (8.6%) | 47 (11.9%) | 0.85 (0.69–1.03) (not significant) | | CPC at 90 d | 1 (1–5) | 1 (1–5) | | Modified Rankin Score at 90 d# | 2 (0–6) | 1 (0–6) | | Montreal Cognitive Assessment score at 90 d | 27 (24–29) | 27 (24–28) | | Neuron‐specific enolase at 48 h* | 17 (11–36) | 18 (11–34) |

*CPC 1: Good cerebral performance: conscious, alert, able to work, might have mild neurologic or

psychological deficit

Modified Rankin Score 1: No significant disability despite symptoms; able to carry out all usual duties and activities

Modified Rankin Score 2: Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance

Adverse events

There was no difference in pre-specified adverse events. The most frequent adverse events included infection, bleeding, and seizures. No difference was observed in the primary outcome on pre-specified subgroup analysis of gender, age, presence of hypertension, renal impairment, COPD, STEMI, and shockable vs. non-shockable rhythm,

Strengths

• Adequately powered
• Groups well matched at baseline
• The largest RCT so far that has addressed the question of oxygenation targets following cardiac arrest.

Limitations

• The target PaO2 levels were attained after reaching the hospital, usually after admission to ICU. Separation in oxygen levels was achieved 2 h after ICU admission. This may be too late, especially because reperfusion injury and hyperoxia damage occur early.
• The liberal group also had what may be considered to be within the “normal” oxygenation range (PaO2: 68–75 vs 98–105 mm Hg). There may be no appreciable difference in clinical outcomes within these two ranges. In the restrictive group, the PO2 levels were on the upper limit of the target range. The P/F ratios were generally high, indicating relatively normal gas exchange in both groups.
• The study included only two centres from Denmark.
• Nearly 90% of arrests were witnessed, with bystander CPR in almost 90% – which may be challenging to attain in other settings.
• Lower mortality (28.7 vs. 31.1%) compared to other studies (TTM trials: 50%)
• The 10% difference in the primary outcome may have been too optimistic, resulting in a less-than-ideal sample size.
• Possible bias related to an unblinded study – especially in regard to end-of-life care
• The results may not be extrapolatable to non-cardiac causes
• Physical follow-up was limited due to the Covid pandemic

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• play_arrowDouble Sequential External Defibrillation – A game-changer
  Dr Swapnil Pawar Alternate defibrillation strategies for refractory ventricular fibrillation

Cheskes S, Verbeek PR, Drennan IR, et al. N Engl J Med. 2022 Nov 24;387(21):1947-1956. doi: 10.1056/NEJMoa2207304. Epub 2022 Nov 6. PMID: 36342151.

Blog Written by Dr Jose Chacko

Background

Double sequential (DSED) and vector change (VC) defibrillation have been in use for many years. Observational studies and case reports have switched to these strategies mainly as a last resort in refractory ventricular fibrillation. Early application of DSED or VC may lead to improved rates of defibrillation and return of spontaneous circulation, and thereby, lead to more favorable clinical outcomes. The left ventricle lies posteriorly; hence, a shock delivered through anterior leads may not have an effective impact on some parts of the left ventricle. Fibrillation is most likely to return or fail to terminate after defibrillation in these areas of the left ventricle when standard pad position is used. Change of vector may result in a higher voltage and offers the potential to defibrillate parts of the ventricle that may be relatively inaccessible to conventional pad positioning.

Population and setting

The study was conducted across six paramedic services in Ontario, Canada between March 2018 and May 2022. Adult patients above 18 years of age, who suffered out of hospital cardiac arrest and experienced refractory ventricular fibrillation (VF) were included. Refractoriness was defined as VF or pulseless ventricular tachycardia as the initial rhythm that did not respond to three standard defibrillation attempts between 2-min intervals of cardiopulmonary resuscitation (CPR). Cardiac arrest due to trauma, drowning, hanging, suspected drug overdose, and hypothermia were excluded.

Design

This was a three-group, cluster randomized trial. The study patients received one of three types of defibrillation – conventional, vector-change, or double-sequential defibrillation, based on the randomly assigned intervention for the cluster. Each cluster crossed over to one of the other strategies every 6 months. Each cluster was meant to undergo each of the three strategies at least once.

The three strategies

1. Conventional defibrillation with pads in the antero-lateral position
2. Double-sequential defibrillation: Two shocks administered one after the other with a gap of less than 5 seconds, with pads in the antero-lateral and antero-posterior positions
3. Vector-change defibrillation: The pad position switched to the antero-posterior position after 3 conventional shocks

Common management

Chest compressions were carried out before the placement of pads. Rhythm analysis was performed every 2 minutes. All patients received three standard anteroposterior defibrillations. Subsequent defibrillation was based on assignment to one of the three strategies.

Sample size

The authors assumed a 12% incidence of the primary outcome, survival to hospital discharge. Based on a difference of 8 percentage points in the primary outcome with the modified defibrillation strategies, they calculated a sample size of 930 patients, with 310 in each group.

Results

The study ceased prematurely after the enrolment of 405 patients due to the spread of Covid-19. Out of 405 randomized patients, 136 were assigned to conventional, 144 to VC, and 125 to DSED.

67.9% of out-of-hospital cardiac arrests were witnessed, and 58.0% of the patients received bystander CPR. Other baseline characteristics, including the median response time, the time to administration of the first shock, the duration and number of shocks administered before the return of spontaneous circulation, were similar. The dose of epinephrine, amiodarone, and lignocaine administered was also similar between the three groups.

| Endpoint | Standard | VC | DSED | DSED vs. standard | VC vs. standard | | Survival to hospital discharge | 18/135 (13.3%) | 31/143 (21.7%) | 38/125 (30.4%) | 2.21 (1.33–3.67) | 1.71 (1.01–2.88) | | VF termination | 92/136 (67.6%) | 115/144 (79.9%) | 105/125 (84.0%) | 1.25 (1.09–1.44) | 1.18 (1.03–1.36) | | ROSC | 36/136 (26.5%) | 51/144 (35.4%) | 58/125 (46.4%) | 1.72 (1.22–2.42) | 1.39 (0.97–1.99) | | Modified Rankin Score 2 or less | 15/134 (11.2%) | 23/142 (16.2%) | 34/124 (27.4%) | 2.21 (1.26–3.88) | 1.48 (0.81–2.71) |

Primary outcome: Survival to hospital discharge was significantly higher with both DSED and VC compared to standard defibrillation

Secondary outcomes: Termination of VF was significantly higher with DSED and VC compared to standard defibrillation. Attainment of ROSC was significantly higher with DSED, but not with VC. More favorable neurological outcomes at hospital discharge, assessed using the Modified Rankin Scale was observed with DSED, but not with VC.

Strengths

• Addresses an important clinical question in refractory VF, considering observational studies that suggest efficacy of early application of alternate defibrillation strategies
• The cluster randomized crossover design is most appropriate for a study of this nature
• The quality of CPR was uniform across different groups
• A standard protocol was followed in all three groups
• Outcome assessors were blinded to the defibrillation strategy

Limitations

• The study did not reach the projected sample size due to the spread of Covid-19 during the study period (only 405 patients were enrolled; the calculated sample size was 930)
• Blinding not possible, hence, there is a likelihood of investigator bias. Termination of resuscitation may have occurred more often with standard care. The study does not provide details regarding the duration of resuscitation and the total number of shocks delivered
• The number of patients who survived to hospital discharge were few: 18/135, 31/143, and 38/125 patients in the conventional, vector-change, and double-sequenced defibrillation arms respectively. The small numbers may have led to an overestimation of effect
• The outcomes assessed only until hospital discharge; this may be less than ideal, especially for neurological evaluation
• Bystander CPR was carried out in 58% of cases and the median time between emergency call and first shock was 10 minutes. Other health care settings may not accomplish these endpoints.
• The impact on the primary endpoint of an 8% increase in survival to hospital discharge with the alternate strategies of defibrillation may have been overly optimistic
• For vector-change defibrillation, the fragility index was 1 for survival to hospital discharge, the primary outcome.
• No data were available for co-morbidities and pre-existing therapies.
• Failure to follow the assigned strategy occurred in a few cases.

Recommendation –

We recommend trying DSED in refractory shockable rhythms if the standard defibrillation strategy fails to achieve ROSC.

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• play_arrowTEAM Trial – Early Mobilisation in Intensive Care
  Dr Swapnil Pawar Early Active Mobilization during Mechanical Ventilation in the ICU* The TEAM Study Investigators and the ANZICS Clinical Trials Group

Blog Written by – Dr Jose Chacko

Population and setting

The study was held from February 27, 2018, to November 19, 2021, across 49 hospitals in 6 countries, including Australia, New Zealand, Ireland, the UK, Germany, and Brazil. Patients were on mechanical ventilation. Ventilation was expected to continue beyond the calendar day after randomization. Patients were judged to be stable to enable mobilization.

Could be on norepinephrine ≤0.2 mcg/kg/min, respiratory rate ≤45/min PEEP ≤16

Excluded

Dependence for activities of daily living in the month preceding hospitalization; orders for bed rest, acute brain or spinal cord injury

Intervention

Early mobilization

Minimization of sedation and physiotherapy in one or two sessions. The highest level of therapy is followed by scale down in case of fatigue. Validation scale of 0–10, 0 for immobility and 10 for walking independently.

Attempt to mobilize patients out of bed (IMS ≥3). This corresponds to sitting over the edge of with trunk control; assistance by staff if required.

Exercises on the bed itself if they did not meet the criteria for out-of-bed mobilization.

Control

Usual care and level of mobilization are generally provided at each site and carried out by a different set of staff if possible.

The trial protocol was continued for the duration of the ICU stay for up to 28 days after randomization.

Sample size

The primary outcome was days alive and out of hospital at 180 days. The sample size was calculated for 90% power to detect a 7-day difference in the primary outcome, with a two-sided alpha of 0.05. Allowing a nonparametric distribution and 5% loss to follow-up, the calculated sample size was 750 patients.

Results

A total of 750 patients were randomized. The primary outcome data were available 369/372 patients in the early mobilization group and 364/378 patients in the usual care group. Patients were well-matched at baseline. Approximately 62% of patients were on some dose of vasopressors and 22% on RRT. 97% of patients were on infusion with sedative agents.

The mean daily duration of active mobilization: 20.8±14.6 vs. 8.8±9.0 minutes in the usual care. (Absolute difference, 12 minutes per day; 95% confidence interval [CI], 10.4 to 13.6).

Process-of-care measures: tracheostomy, neuromuscular blockers, glucocorticoids, new renal-replacement therapy, re-intubation, and vasopressor-free days — were similar in the two groups

| Outcome | Early mobilization (371) | Usual care (370) | Significance | | Alive and out of hospital* at 180 d | 143 days (21–161) | 145 days (51–164) | −2.0 (−10 to 6) p = 0.62 | | Mortality at 180 days | 83/369 (22.5%) | 71/364 (19.5%) | OR, 1.15; 95% CI, 0.81–1.65 | | Number of ventilator-free days from randomization to day 28# | No significant difference | | No of ICU-free days from randomization to day 28# | No significant difference |

*The number of days at home or in accommodation other than a health care facility (rehabilitation hospital or nursing home). Days alive and out of hospital at 180 days = 0 if death occurred before 180 days

The number of ventilator-free and ICU-free days at day 28 counted as zero if death occurred before 28 days

Patient-reported outcome measures, including quality of life and function in survivors, were

evaluated at day 180.

The following indices were used to assess the quality of life

• The EQ Visual Analogue Scale provided a global rating of patient-perceived health from 0 to 100, with higher scores indicating better health
• Barthel Activities of Daily Living (ADL) Index
• Lawton Instrumental Activities of Daily Living Scale (IADL)
• World Health Organization Disability Assessment Schedule (WHODAS 2.0)

Patient-reported outcomes were available in 286 patients in the early-mobilization group and 293 in the usual-care group. Findings regarding the quality of life, activities of daily living, and disability were similar between groups

Adverse events

Evaluated prespecified adverse events, including falls to the floor, cardiac arrest, atrial fibrillation with a ventricular response of more than 150 bpm, other dangerous arrhythmias, oxygen-saturation level on pulse oximetry of less than 80% for more than 3 minutes, and unplanned extubation or removal of the intravascular line resulting in urgent replacement.

Adverse events that were potentially due to mobilization (arrhythmias, altered blood pressure, and desaturation) were reported in 34 of 371 patients (9.2%) in the early-mobilization group and in 15 of 370 patients (4.1%) in the usual-care group (P=0.005).

Serious adverse events

A total of 8 serious adverse events were reported, of which 7 occurred in the early-mobilization group (5 arrhythmias, a desaturation episode, and a cerebrovascular accident), and 1 occurred in the usual-care group (a desaturation episode). All serious adverse events required intervention. All were reversed except for the patient with a cerebrovascular accident who had a persistent weakness. No incidence of falls, cardiac arrest, unplanned extubation, or intravascular line removal resulting in urgent replacement

Comments/limitations

• Some patients in the cohort could not be mobilized according to plan
• Missing data (withdrew consent or lost to follow up)
• Does the “usual care” of the study apply to a general ICU setting?
• Would a specific subgroup of patients benefit from early mobilization?
• More research required to decide on timing, intensity, and duration of mobilization
• Important to note that the study compared two levels of mobilization and found no difference on outcomes. It should not be inferred that early mobilization is not beneficial. Besides, although the duration of mobilization was greater in the early group, the intensity was similar in both groups. This may have contributed to the apparent lack of benefit with early mobilization.
• The difference between early mobilization and usual care may have been not substantially different in some of the centers
• Will a mobilization strategy focused during ICU stay alone make a difference? Perhaps more crucial would be the rehabilitation phase once out of the ICU
• The primary outcome of days alive and out of hospital at 180 days may be an unrealistic outcome to aim for with an early mobilization strategy.

Our recommendation –

It’s essential not to STOP mobilising your patients based on the trial results.

It will be helpful to personalise early mobilisation strategies in a select subgroup of patients to avoid adverse events associated with early mobilisation.

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play_arrow SETPOINT 2 Trial – Early Vs Late Tracheostomy in Stroke patients Dr Swapnil Pawar   Blog Written by – Dr Jose Chacko Effect of Early vs Standard Approach to Tracheostomy on Functional Outcome at 6 Months Among Patients With Severe Stroke Receiving Mechanical Ventilation The SETPOINT2 Randomized Clinical Trial [...]

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play_arrow WATERFALL Trial – Fluid Resuscitation in Acute Pancreatitis Dr Swapnil Pawar   Written by – Dr Jose Chacko Aggressive or Moderate Fluid Resuscitation in Acute Pancreatitis Hypoperfusion and hemoconcentration in acute pancreatitis may lead to necrosis, and adverse clinical outcomes. Population The WATERFALL multicenter, open-label, parallel-group, randomized, controlled, superiority [...]

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play_arrow Tranexamic Acid in ICU Dr Swapnil Pawar In this episode, we discuss various indications and the evidence behind each indication for using Tranexamic acid in ICU. Key indications that we discuss – Trauma Traumatic brain injury Post-partum hemorrhage Cardiothoracic surgery GI bleed

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play_arrow Oxygen Therapy in Intensive Care Dr Swapnil Pawar In our landmark 100th episode, we discuss the controversy around one of the most commonly used drugs in intensive care, i.e. Oxygen. In this episode, we dive deeper into the available evidence and recommend our approach for using oxygen in critically [...]

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play_arrow Targeted Temperature management in TBI Dr Swapnil Pawar In this episode, we discuss the role of therapeutic hypothermia and targeted temperature management in severe TBI. We dive deeper into the available literature on this topic and share our recommendations on this controversy. The key controversies on this topic include [...]

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play_arrow Ventilator Associated Pneumonia Dr Swapnil Pawar Ventilator-associated Pneumonia Blog Written by Dr Jose Chacko CDC definitions Ventilator-associated event (VAE) Ventilator-associated condition (VAC): increase in daily minimum PEEP ≥ 3 cm H2O or FiO2  ≥ 0.20 sustained for at least 2 calendar days following a baseline period (2 calendar days) [...]

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The CLASSIC trial  Blog written by Dr Jose Chacko  Setting and design The CLASSIC trial was a multicentric randomized clinical trial carried out in 31 ICUs in Denmark, Norway, Sweden, Switzerland, Italy, the Czech Republic, the United Kingdom, and Belgium. The study was conducted over a 3-year period between November [...]

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play_arrow LOVIT trial – Final Nail in the Coffin for Vit C in Septic Shock? Dr Swapnil Pawar Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit Blog Written by Dr Jose Chacko Setting   Thirty-five medical–surgical ICUs in Canada, France, and New Zealand.   Included: Adult [...]

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play_arrow Resuscitation Targets in Septic Shock Dr Swapnil Pawar In this podcast, we discuss the evidence behind different resuscitation targets used in the treatment of a patient with septic shock Lactate Capillary refill time MAP Echo/USG based measurements. Microcirculation assessment Our strategy – A multimodal approach to resuscitation of a [...]

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play_arrow eCPR in Out of Hospital Cardiac Arrest Dr Swapnil Pawar Effect of Intra-arrest Transport, Extracorporeal Cardiopulmonary Resuscitation, and Immediate Invasive Assessment and Treatment on Functional Neurologic Outcome in Refractory Out-of-Hospital Cardiac ArrestA Randomized Clinical Trial Blog written by Dr Jose Chacko Design and setting The study was conducted over [...]

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play_arrow Noradrenaline Vs Adrenaline in OHCA Patients Dr Swapnil Pawar Epinephrine versus norepinephrine in cardiac arrest patients with post-resuscitation shock (Bougouin et al. Intensive Care Med. 2022 Mar;48(3):300-310) Blog Written by – Dr Jose Chacko Study population and design: In this registry-based observational study, the authors identified patients admitted alive [...]

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play_arrow NIV in COVID-19 Dr Swapnil Pawar NIV In COVID-19 Written by Dr Jose Chacko and Dr Swapnil Pawar Current Guidelines –  Available Evidence –  RECOVERY-RS Trial  Does CPAP or HFNO, compared with conventional oxygen therapy, reduce the need for tracheal intubation or mortality within 30 days in COVID-19-related acute [...]

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play_arrow Long Term Outcomes in COVID-19 Dr Swapnil Pawar Clinical Outcomes Among Patients With 1-Year Survival Following Intensive Care Unit Treatment for COVID-19 Heesakkers H, van der Hoeven JG, Corsten S, et al. JAMA. 2022 Feb 8;327(6):559-565. doi: 10.1001/jama.2022.0040. Blog Written by Dr Jose Chacko Design and study population This [...]

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play_arrow PLUS Study Dr Swapnil Pawar Join us for our 90th episode of the eCritCare podcast, where Jose Chacko & I discuss the recently published landmark trial PLUS. This trial demonstrated no significant difference in 90-day mortality between the saline group and the plasmalyte-148 group. It raises the question – Does the [...]

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play_arrow MICHELLE Trial – Rivaroxaban in COVID-19 Dr Swapnil Pawar Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre, randomised, controlled trial Blog Written by – Dr Jose Chacko Question: In patients hospitalized with COVID-19, does prophylaxis with rivaroxaban 10 mg/day for 35 days [...]

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play_arrow Omicron Variant – Facts and Challenges Dr Swapnil Pawar In this episode, we discuss the challenges faced by healthcare systems and the patterns emerging from the current COVID-19 pandemic wave caused by the Omicron variant. Blog Written by – Dr Jose Chacko The World Health Organization reported on omicron [...]

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play_arrow ICU Journal Club- COVID HighFlow Dr Swapnil Pawar Effect of High-Flow Oxygen Therapy vs Conventional Oxygen Therapy on Invasive Mechanical Ventilation and Clinical Recovery in Patients With Severe COVID-19A Randomized Clinical Trial Blog written by Dr Jose Chacko Design and setting Randomized controlled trial conducted across three centers in [...]

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play_arrow Glycemic Control in ICU Dr Swapnil Pawar Blog Written by Dr Jose Chacko Uncontrolled hyperglycemia may adversely impact critically ill patients through diverse mechanisms. High glucose levels may impair the innate immune response, with abnormal glycosylation of immunoglobulins.1 Neutrophil migration is inhibited with suppression of phagocytic activity; complement fixation and [...]

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play_arrow ICU Journal Club – CONTROLING Study Dr Swapnil Pawar Individualised versus conventional glucose control in critically ill patients: the CONTROLING study—a randomized clinical trial Blog written by Dr Jose Chacko Background –  Hyperglycaemia is an adaptive response to stress and is commonly seen in critically ill patients. Individualising hyperglycaemia [...]

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Early Vs Delayed RRT in ICU

Dr Swapnil Pawar

Blog Written by Dr Jose Chacko Intensive care physicians often face the conundrum of deciding when to consider renal replacement therapy (RRT) in acute kidney injury (AKI). RRT may be commenced for the early correction of metabolic complications and prevention of volume overload. However, an early strategy may entail unnecessary therapy for some patients who might recover renal function otherwise. Even more concerning is the perpetuation of damage that may occur due to the hemodynamic instability that often accompanies RRT. The proximal tubules located at the corticomedullary junction are particularly vulnerable to ischemic insult. The partial pressure of oxygen at this region is less than 40 mm Hg, which increases the susceptibility of the tubular cells to RRT-induced damage (1). Hence it is critically important to decide on the requirement for RRT and to initiate therapy at the optimal time.

Renal replacement therapy: benefit vs. possible harm

The likelihood of benefit compared to the possibility of harm must be carefully weighed prior to the commencement of RRT. Particularly, in patients with no life-threatening complications and those with a reasonable likelihood of recovery, RRT may worsen renal function and may be independently associated with increased mortality (2,3). More than three decades ago, Conger et al. proposed that the potential benefits of early, aggressive RRT may be offset episodic intra-dialytic hypotension that may perpetrate recurrent ischemic insult and affect recovery from renal failure (4). Although less common compared to intermittent therapies, hypotensive episodes may still occur with continuous therapies (5). In the BEST trial, hypotension occurred in 19% of patients who underwent CRRT (6). Other complications of RRT include those related to vascular access and inappropriate antibiotic dosage, especially considering the lack of adequate information regarding optimized dosing (7). Besides, excessive loss of electrolytes and essential nutrients may occur (8). The dialytic membrane and the extracorporeal circuit may evoke an inflammatory response and lead to potential harm (9). The poor predictive ability to discern the possibility of harm from delayed initiation of RRT adds further complicity to the clinical scenario.

Many of the older studies that support early RRT have been observational (10); besides, the overall management of critically ill patients has changed considerably over the years. Hence, it is appropriate to reconsider the impact of the timing of RRT, particularly with new information available from the more recent randomized controlled studies (RCTs) (Table 1).

Table 1. RCTs evaluating the timing of RRT

Early vs. late: the evidence

The ELAIN trial

The ELAIN trial involved 231 postoperative patients (47% cardiac surgical) with AKI from a single center in Germany (11). The early group was randomized to receive RRT within 8 h of the diagnosis of AKI, KDIGO stage 2; the late group was randomized to undergo RRT within 12 h of reaching KDIGO stage 3. Besides, at least one of the following conditions had to be present, including severe sepsis, catecholamine use, refractory fluid overload, and new-onset or worsening of non-renal organ dysfunction. All 112 patients randomized to the early group received RRT, compared to 108/119 patients in the late group. The 90-d mortality, the primary outcome, was significantly lower in the early group. Approximately 75% of all patients had evidence of fluid overload according to the pre-defined criteria. This raises the question of whether RRT may have been delayed among patients who had evidence of fluid overload but were randomized to the late group, leading to worse outcomes in this group of patients. Besides, the fragility index for the primary outcome was only 3 patients (the results would have been non-significant if 3 extra patients had suffered 90-day mortality in the early group). Furthermore, it is hard to explain a mortality benefit at 90 d, with no difference in the 28 and 60 d mortality.

The AKIKI trial

Patients in KDIGO stage 3 were randomized to receive early or late RRT in the AKIKI trial (12). In the early group, RRT was initiated immediately after randomization. In the late group, RRT was performed if any of the following criteria were present: K+ > 6.0 mmol/l (> 5.5 mmol/l after corrective measures), BUN > 112 mg/dl, pH < 7.15, and acute pulmonary edema due to fluid overload). In the early group, 305/311 (98.1%) received RRT, while only 157/308 (51%) patients in the late group underwent RRT. There was no significant difference in mortality between groups on day 60, which was the primary outcome of the study. Thus, nearly half of all patients who were randomized to the late group did not require RRT and suffered no adverse outcomes.

The IDEAL-ICU trial

The IDEAL-ICU investigators, in a multicentric French study, randomized patients in early-stage septic shock who were in the failure stage (stage F) of the RIFLE classification (13). The early group received RRT within 12 h of documentation of stage F; the late group underwent RRT after 48 h if renal recovery had not occurred in the meantime. The primary outcome was 90-d mortality. The study was stopped for futility after a second interim analysis. No difference was observed in the 90-d mortality between the early and late groups (58% vs. 54%, p = 0.38). In the late group, 38% of patients did not receive RRT.

The STARRT-AKI trial

Critically ill patients with AKI from 168 sites across 15 countries were randomized to receive an accelerated or standard strategy of renal replacement therapy in the STARRT-AKI trial. Patients were included if they had reached KDIGO stage 2 or 3 and the treating physician considered that there was sufficient equipoise in choosing between an accelerated compared to a standard strategy. In the accelerated strategy group, RRT was commenced within 12 h of randomization. In the standard strategy group, RRT was initiated in the presence of metabolic acidosis (pH <7.2, or HCO3 <12 mmol/l), hyperkalemia (K+ >6 mmol/l), fluid overload with hypoxemia, or persistent AKI lasting >72 h after randomization. The primary outcome was the 90-d mortality; there was no difference between the accelerated compared with the standard strategy of RRT (43.9% vs. 43.7%; RR: 1, [95% CI 0.93-1.09], P = 0.92). RRT dependence at 90 days after randomization was significantly higher in the accelerated compared to the standard strategy group (10.4% vs 6%), RR 1.74 [95% CI 1.24-2.43]). Adverse events, including hypotension and hypophosphatemia, were more common with the accelerated strategy. No differences were observed between groups in the composite of all-cause mortality and RRT-dependence at 90 days. The ICU, 28-d, and hospital mortality were also similar between the two groups. The number of RRT-free days at 90 days, and the ventilation-free days, and vasopressor-free days at 28 days were also not significantly different between the two groups. This study demonstrated no improvement in the 90-d survival with an accelerated strategy of RRT; besides, it suggested increased RRT-dependence at 90 days compared to a standard strategy.

The AKIKI-2 trial

The AKIKI 2 trial compared two delayed strategies in critically ill patients who were on mechanical ventilation or catecholamine infusion and in KDIGO stage 3 of AKI. Patients were oliguric or anuric (urine output <0·3 ml/kg/h or <500 ml/day for > 72 h) or had a blood urea nitrogen level between 112–140 mg/dl. RRT was carried out within 12 h after meeting the above criteria (delayed group) or postponed until the blood urea nitrogen concentration level reached 140 mg/dl, or an urgent requirement for RRT arose in the meantime (more delayed group). The primary outcome was the number of RRT-free days until day 28; there was no significant difference between the delayed and more-delayed strategies (12 vs. 10 days; P = 0.93). On multivariable analysis, one of the risk factors associated with 60-d mortality was a more-delayed strategy; other risk factors were a higher SAPS III score and the requirement for mechanical ventilation. RRT-dependence at 60 days and complications potentially resulting from acute kidney injury or RRT were similar between groups.

Summary

Apart from the ELAIN trial, other RCTs suggest that in the absence of life-threatening complications, a delayed strategy may be appropriate in most patients with AKI. Such a strategy may facilitate avoidance of RRT, with its associated complications. These studies reinforce the view that initiation of RRT should not be based on the AKI stage; it may be more appropriate to be guided by the presence of complications, including fluid overload and metabolic abnormalities. Furthermore, a strategy of watchful waiting may enhance the possibility of renal recovery. In contrast, RRT-related hemodynamic instability may lead to worsening or perpetuation of renal damage and adversely impact recovery.

It is also important to assess the trajectory of the underlying disease process and the presence of failure of other organs while considering RRT. If the patient is clinically improving with the resolution of other organ failures, perhaps a waiting strategy would be more appropriate. However, if the metabolic demands continue to remain high with a continued requirement for fluid resuscitation, it may be appropriate to consider early RRT. In such situations, the metabolic and fluid demands far exceed the capacity of the kidney, necessitating prompt supportive therapy. The “frusemide test” was used to identify patients who are likely to require renal replacement therapy in a previous study (14). It involves the administration of intravenous frusemide, 1.0 mg/kg to frusemide-naïve patients and 1.5 mg/kg to those already on frusemide. A urine output of less than 200 ml in the ensuing 2 h was highly predictive of patients who required RRT.

References

1. Gaudry S, Quenot J-P, Hertig A, Barbar SD, Hajage D, Ricard J-D, et al. Timing of Renal Replacement Therapy for Severe Acute Kidney Injury in Critically Ill Patients. Am J Respir Crit Care Med [Internet]. 2019 Feb 20 [cited 2019 Mar 21]; Available from: https://www.atsjournals.org/doi/10.1164/rccm.201810-1906CP

2. Clec’h C, Gonzalez F, Lautrette A, Nguile-Makao M, Garrouste-Orgeas M, Jamali S, et al. Multiple-center evaluation of mortality associated with acute kidney injury in critically ill patients: a competing risks analysis. Crit Care Lond Engl. 2011;15(3):R128.

3. Elseviers MM, Lins RL, Van der Niepen P, Hoste E, Malbrain ML, Damas P, et al. Renal replacement therapy is an independent risk factor for mortality in critically ill patients with acute kidney injury. Crit Care Lond Engl. 2010;14(6):R221.

4. Conger JD. Does Hemodialysis Delay Recovery from Acute Renal Failure? Semin Dial. 1990;3(3):146–8.

5. Shawwa K, Kompotiatis P, Jentzer JC, Wiley BM, Williams AW, Dillon JJ, et al. Hypotension within one-hour from starting CRRT is associated with in-hospital mortality. J Crit Care. 2019 Dec;54:7–13.

6. Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005 Aug 17;294(7):813–8.

7. Fissell WH. Antimicrobial dosing in acute renal replacement. Adv Chronic Kidney Dis. 2013 Jan;20(1):85–93.

8. Finkel KW, Podoll AS. Complications of continuous renal replacement therapy. Semin Dial. 2009 Apr;22(2):155–9.

9. Gutierrez A, Alvestrand A, Wahren J, Bergström J. Effect of in vivo contact between blood and dialysis membranes on protein catabolism in humans. Kidney Int. 1990 Sep;38(3):487–94.

10. Bagshaw SM, Uchino S, Bellomo R, Morimatsu H, Morgera S, Schetz M, et al. Timing of renal replacement therapy and clinical outcomes in critically ill patients with severe acute kidney injury. J Crit Care. 2009 Mar;24(1):129–40.

11. Zarbock A, Kellum JA, Schmidt C, Van Aken H, Wempe C, Pavenstädt H, et al. Effect of Early vs Delayed Initiation of Renal Replacement Therapy on Mortality in Critically Ill Patients With Acute Kidney Injury: The ELAIN Randomized Clinical Trial. JAMA. 2016 May 24;315(20):2190.

12. Gaudry S, Hajage D, Schortgen F, Martin-Lefevre L, Pons B, Boulet E, et al. Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit. N Engl J Med. 2016 Jul 14;375(2):122–33.

13. Barbar SD, Clere-Jehl R, Bourredjem A, Hernu R, Montini F, Bruyère R, et al. Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis. N Engl J Med. 2018 Oct 11;379(15):1431–42.

14. Lumlertgul N, Peerapornratana S, Trakarnvanich T, Pongsittisak W, Surasit K, Chuasuwan A, et al. Early versus standard initiation of renal replacement therapy in furosemide stress test non-responsive acute kidney injury patients (the FST trial). Crit Care Lond Engl. 2018 Apr 19;22(1):101.

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ICU Journal Club- COVID STEROID 2 Trial

Dr Swapnil Pawar

Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe HypoxemiaThe COVID STEROID 2 Randomized Trial Question –

What is the effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life support at 28 days inpatients with COVID-19 and severe hypoxemia?

Setting and design

The COVID-STEROID-2 randomized controlled trial was conducted between August 27, 2020, and May 20, 2021, including 11 centres in Denmark, 12 in India, two in Sweden, and one in Switzerland. Stratified randomization by trial site, age less than 70 years, and requirement for invasive ventilation at screening. Patients were randomized in a 1:1 ratio to receive 6 vs. 12 mg dexamethasone.

Study population

Inclusion

Patients with confirmed SARS-CoV-2 infection who required oxygen at a flow rate of at least 10 L/min, NIV or CPAP, or were intubated and ventilated.

Exclusion

Glucocorticoids in doses higher than 6 mg of dexamethasone or equivalents for non-covid indications; on glucocorticoids for COVID-19 for 5 days or longer; the presence of invasive fungal infection or active tuberculosis; history of hypersensitivity reactions to dexamethasone; pregnancy

Interventions

Low-dose arm

Dexamethasone 6 mg IV up to 10 d after randomization

High-dose arm

Dexamethasone 12 mg IV up to 10 d after randomization

Other treatment modalities were left to the best judgement of clinicians. Other immunosuppressive agents were discouraged. Tocilizumab was allowed from January 2021 after the publication of the REMAP-CAP trial results.

Sample size

1000 patients for a 15% relative reduction in the 28-day mortality, 10% relative reduction in the time requiring life support, with 85% power.

1414 were screened, 414 were excluded

62% patients were recruited from Europe and 38% from India

Baseline characteristics

12 mg vs. 6 mg

Supplemental oxygen 55 vs. 53%

NIV or CPAP 24 vs. 26%

Invasive ventilation 22 vs. 20%

Other baseline characteristics were similar, except diabetes, higher in the 6 mg group.

Primary outcome

Composite outcome: alive and free of life support (free of invasive ventilation, circulatory support, and RRT)

Median number of days alive without life support at 28 days after randomization: 22.0 vs. (IQR, 6.0-28.0) 20.5 days (IQR, 4.0-28.0) days (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days], P = 0.07

Alive and free of life support as percentage of patients: 42.6% vs. 40.2%

Individual components of the composite primary outcome

Days alive without invasive mechanical ventilation

Days alive without circulatory support

Days alive without RRT

No difference on adjusted analysis (adjusted for baseline comorbidities including ischemic heart disease or heart failure, diabetes, chronic obstructive pulmonary disease, use of immunosuppressive therapy within the prior 3 months, use of circulatory support, and use of kidney replacement therapy)

Secondary outcomes

No. of days alive without life support at 90 d, median: 84 vs. 80 days

No. of days alive and out of hospital at 90 d, median: 61.5 vs. 48 days

28-d mortality: 27.1% vs. 32.3% (not statistically significant)

90-d mortality: 32% vs. 37.7% (not statistically significant)

Serious adverse events (not different)

New episodes of septic shock

Invasive fungal infection

Clinically important gastrointestinal bleeding

Anaphylactic reaction to dexamethasone

Strengths –

1. Pragmatic trial
2. A relatively large number of patients
3. Conducted across 2 different continents – good external validity
4. Blinding, allocation concealment and good follow up rate – good internal validity

Limitations –

• The presumed difference in outcomes between groups (15% relative reduction in the 28-day mortality, 10% relative reduction in the time requiring life support) may have been too large; a trend towards improved 28- and 90-d survival. The sample size may have been too small; hence the possibility of type II error.
• Composite primary outcome – underpowered
• The frequentist approach itself may be inferior to the bayesian approach for such a trial.
• Mortality among subgroups: especially at different levels of respiratory support may have been useful
• Concomitant use of tocilizumab halfway through may have confounded the results.

Take- home –

This trial has added significant information on the role of steroids in COVID-19 however, it fails to change the current practices.

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Surviving Sepsis Campaign Guidelines

Dr Swapnil Pawar

Blog Written by Dr Jose Chacko Screening and early treatment

Recommendation against qSOFA

The qSOFA screening parameters include a systolic BP <100 mm Hg, respiratory rate >22, and a GCS <15. The presence of 2 or more criteria denotes a positive qSOFA.

The SSG make a strong recommendation against the use of qSOFA as a single screening tool, compared to the National Early Warning Score (NEWS), Modified Early Warning Score (MEWS), or the systemic inflammatory response syndrome (SIRS) considering its poor sensitivity for the diagnosis of sepsis. This recommendation is mainly based on systematic reviews that have shown that qSOFA has a high specificity and predictor of poor outcomes, but low sensitivity for the diagnosis of sepsis.

Lactate measurement and lactate-guided resuscitation

The SSG make a weak recommendation for the measurement of lactate levels among patients suspected of sepsis. This is largely based on a good correlation between raised lactate levels and the likelihood of sepsis. However, the lactate level must be interpreted based on the clinical situation; it is neither sensitive nor specific to confirm or exclude the diagnosis of sepsis. The most common reason for raised lactate levels is probably due to adrenergic stimulation and stimulation of cAMP leading to increased aerobic glycolysis and activation of Na+–K+ ATPase pump. This leads to a rise in pyruvate levels which overwhelms the capacity of pyruvate dehydrogenase that converts pyruvate to acetyl CoA. Instead, lactic dehydrogenase converts pyruvate to lactate. Lactate levels may also rise due to hepatic dysfunction, release from the lung in the presence of acute respiratory distress syndrome, and epinephrine administration to support the circulation.

Although hyperlactatemia is a marker of adverse outcomes, raised lactate levels in sepsis is usually not due to reduced oxygen delivery with triggering of anaerobic metabolism. In fact, lactate may be an important substrate for the heart and the brain for aerobic energy production.

The 2016 guidelines had recommended initial resuscitation aimed to target normal lactate levels. However, the 2021 guidelines have revised this recommendation and favour the guidance of resuscitation aimed to decrease (not normalize) lactate levels. This is based on the realization that normal lactate levels may not be achievable in many septic patients during the early phase of resuscitation.

Fluid resuscitation

How much fluid is part of initial resuscitation?

The 2021 guidelines continue to recommend fluid resuscitation with 30 ml/kg of a balanced crystalloid solution over the first 3 hours. The level of recommendation has been upgraded from weak to strong. This recommendation in based on a retrospective study, and the mean volume of resuscitation fluid administered prior to randomization of patients in the ARISE, PROCESS, and PROMISE trials that evaluated early goal-directed therapy in sepsis. The mean volume of initial resuscitation in these trials was 27 ml/kg.1

The requirement of volume resuscitation is likely to be highly variable in septic patients. Although 30 ml/kg may be reasonable, to begin with, a fixed volume is clearly not optimal in all settings.

In the three-armed FEAST trial, children with evidence of hypoperfusion related to sepsis were randomized to receive a bolus of normal saline, 5% albumin, or no fluid. The 48-hour and 4-week mortality were significantly higher among children who received either fluid bolus compared to those who received no bolus fluid.2 In a randomized control trial of septic patients in Zambia, patients received protocolized resuscitation including intravenous fluids, blood transfusions for a hemoglobin level of <7 g/dl, and vasopressors for a target mean arterial pressure (MAP) ≥65 mm Hg or usual care. The median volume of fluid administered was 3.5 L (IQR, 2.7-4.0 L) in the protocolized care group compared to 2.0 L (IQR, 1.0-2.5 L) in the usual care group. In-hospital mortality, the primary outcome, was significantly higher in the protocol-based care group that received a higher volume of intravenous fluids (48.1% vs. 33%; RR: 1.46, 95% CI: 1.04-2.05). These studies suggest that overzealous, fixed volume fluid resuscitation during the initial phase of sepsis may lead to adverse clinical outcomes.

After initial resuscitation, the guidelines recommend further administration of fluid based on dynamic parameters. A Scandinavian multicentric randomized controlled trial evaluated this question among 151 patients. In the standard care group, patients could continue to receive continued fluid boluses if the hemodynamic variables improved based on dynamic or static indices. In the fluid-restrictive arm, additional boluses were administered only if the lactate level was >4 mmol/l, the MAP was <50, skin mottling was present below the knee, or the patient was oliguric in the first 2 hours after randomization. This pilot study demonstrated that a restrictive protocol resulted in a significant reduction in the resuscitation volume. Although not powered to evaluate clinical outcomes, the use of a restrictive strategy resulted in a significantly lower incidence of worsening of acute kidney injury during the 90-day follow-up period. There was no significant difference in the incidence of ischemic events, days alive without ventilator support, or renal replacement therapy.

The question remains unanswered if an arbitrary volume of bolus fluid is administered within a fixed period as part of a general approach, would this lead to iatrogenic fluid overload in a significant number of patients?

What type of fluid?

A balanced crystalloid is preferred over normal saline during the initial resuscitation phase. This recommendation is based on the SALT-ED and the SMART randomized controlled trials that demonstrated worse clinical outcomes with the use of normal saline compared to a crystalloid.3,4 The recently published BaSICS trial compared plasmalyte to normal saline in critically ill patients who required fluid resuscitation in 75 ICUs in Brazil. No difference was noted in the 90-day mortality, the primary outcome of the study. Besides, the incidence of acute kidney injury requiring renal replacement therapy was also not different between groups. Further research regarding the resuscitation fluid is warranted, considering these contrasting reports.

Antibiotics

How soon should antibiotics be administered?

The SSG recommend antibiotic administration with an hour in patients presenting with septic shock and within 3 hours in patients with sepsis without shock. This is a departure from the previous guideline that recommended a 1-hour time frame in both situations. There is no argument that timely administration of antibiotics in septic patients is crucial in improving outcomes. However, setting a short, rigid timeframe may likely lead to logistical problems and overtreatment with antibiotics among patients who may not have an infective illness, considering the limited time available to arrive at a definitive diagnosis in a busy emergency department.

Alam et al. compared the effect of antibiotic administration by ambulance personnel with usual care involving antibiotic administration in the emergency department in patients with sepsis. In the early administration group, the median time to antibiotic administration was 26 min before presentation at the emergency department; in the usual care group, it was 70 minutes after arrival. There was no difference in the primary outcome of 28-day mortality between groups, regardless of the severity of illness.5

Monotherapy vs. combined therapy

The new guidelines recommend empiric therapy with two antimicrobials in situations with a high risk for multidrug-resistant organisms and monotherapy if the risk is low. Both are categorized as weak recommendations with a very low quality of evidence. Therapy should be scaled down to a single antibiotic once sensitivity reports are available. Although a rational recommendation, there is scant evidence to support the use of combination therapy in septic patients. A meta-analysis of randomized controlled trials revealed no difference in mortality or other patient-centred outcomes among patients who received monotherapy compared with combination antibiotic therapy in patients with severe sepsis.6

What should be the target mean arterial pressure (MAP)

The SSG recommends a target MAP of 65 mm Hg over higher targets for septic patients receiving vasopressors. This recommendation is based on the study by Lamontagne et al. with titration of vasopressors to a target MAP of 60–65 mm Hg, compared to usual care in patients with vasodilatory shock. There was no difference in the 90-day mortality between groups; exposure to vasopressors was significantly lower when a lower MAP of 60–65 mm Hg was targeted.7 However, in the SEPSISPAM trial, a target MAP of 80-85 compared to 65–70 mm Hg resulted in a significantly lower requirement for renal replacement therapy among patients with chronic hypertension, although there was no difference in the 28- and 90-day mortality.8 Assiduous adherence to fixed targets of MAP may not be appropriate; a flexible approach with a focus on measures of perfusion is likely to be more optimal.

Oxygenation targets

Considering the lack of robust evidence, the SSG does not make any recommendation regarding oxygenation on sepsis-induced respiratory failure. Several randomized controlled trials have addressed this question. The ICU-ROX study randomized critically ill patients to a conservative SaO2 target of 91–96% compared to usual care, with SaO2, maintained between 91–100%. No difference was noted between groups in the number of ventilator-free days at day-28, and mortality at 90 and 180 days. However, a post-hoc analysis revealed a trend towards improved survival at 90-days among septic patients who received usual care (higher SaO2).9 This hypothesis needs to be tested in future controlled trials.

Time to ICU admission

A 6-hour window is suggested for admission to the ICU in patients suspected to have sepsis. There is strong evidence that delay in ICU admission from the wards10 or the emergency department11 leads to adverse outcomes in septic patients. The 6-hour timeline recognizes time and space constraints, especially in lower and middle-income countries. Although a 6-hour timeframe is suggested, it is important to emphasize the identification of septic patients early and prioritize admission to ICU to optimize clinical outcomes.

Summary –

SSCG 2021 is a good guide for clinicians. However, clinicians should use a personalised approach in treating patients with sepsis and septic shock.

The post Surviving Sepsis Campaign Guidelines first appeared on Critical Care Education.

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The Role of Hyperventilation in ICP Control

Dr Swapnil Pawar

Management of arterial partial pressure of carbon dioxide in the first week after traumatic brain injury: results from the CENTER-TBI study Written by – Dr Jose Chacko & Dr Swapnil Pawar

Context –

Recent BTF Guidelines suggested the use of Hyperventilation (HV) to target PaCO2 32–35 mmHg for controlling ICP only as a second-tier treatment. These guidelines did not support lower PaCO2 levels and recommended against routine hyperventilation to PaCO2 below 30 mmHg.

However, the practices vary across the globe.

Objectives –

1. to assess, in a real-world context, PaCO2 management and the lowest target of PaCO2 in a large cohort of mechanically ventilated TBI patients and
2. To assess practice variability between centres to evaluate the association between the use of profound HV and 6-month clinical outcomes.

Setting and design

The CENTER-TBI core study is a prospective observational study across centers in Europe that addressed the epidemiology, management and outcomes after TBI, conducted over a 3-y period between 2014–2017. The current study was performed to evaluate the management of PCO2 in patients with severe TBI, and optimal PCO2 targets in relation to clinical outcomes

Subjects

1176 patients with TBI from 51 centers who were intubated, ventilated and had at least 2 arterial PCO2 values in the first 7 days. From this cohort, 1100 patients were included from centers that enrolled at least 10 patients. The median age was 48 (29–64) years, 64.7% of patients had severe TBI (GCS 8 or less). The baseline PCO2 was 39.1 mm Hg. ICP monitoring was carried out in 68% of patients.

To adjust for confounders, the propensity of centers to use profound hypocapnia was evaluated measured as the relative proportion of PCO2 <30 mm Hg. This was included in a logistical regression model.

Results

The PCO2 levels in the first week varied widely between centers and ranged between a mean level of 32.3 – 38.7. Mean lowest PCO2 in the first week: 35.2 ± 5.4.

Relatively few patients [144, (13%)] patients had all PCO2 between 35–45 (relatively small number of patients who were maintained between the recommended range)

Wide variation was observed in the use of HV

There was a 1.72 fold difference between centers for odds of PCO2 between 35–45.

After exclusion of patients with intracranial hypertension, the difference in the median odds ratio decreased (MOR) to 1.4

Patients who underwent profound HV (PCO2 <30) in the first 7 days ranged between 1–30% between centers

At least one episode of profound hyperventilation (HV) was observed in 36% of patients during the first week. There was considerable variation between centres in the use of profound HV (MOR of 2.0). The use of HV was greater in patients with intracranial hypertension (odds of HV 3 times higher). The use of HV decreased from days 1–7.

Other monitoring modalities including jugular bulb oxygen saturation and brain tissue oxygenation were used infrequently.

Profound HV is associated with more aggressive treatment – as evidenced by a higher therapeutic intensity level (TIL). Patients who underwent profound HV also more likely to undergo decompressive surgery (8.6 vs. 4.8%), and low or high-dose osmotherapy

Clinical outcomes

165/1100 (15%) died in ICU

970 patients had 6-month outcomes available

775/970 (79.9%) had poor outcomes: death or GOSE 4 or less

246/970 (25.4%) died at 6 months

529/970 (54.5%) GOSE 4 or less

In patients with at least one episode of profound HV:

Mortality at 6 months: 29% with profound HV vs. 23% who did not undergo profound HV (p=0.045)

GOSE 4 or less: 64% vs. 49% (p <0.001)

On instrument variable analysis the propensity to use profound HV did not impact mortality or unfavorable outcome, after adjusting for the level of intracranial pressure. After adjustment for baseline variables, no difference in mortality or 6-month outcomes with the use of HV

Centres that used profound HV more often, (by 10%) had numerically higher odds for mortality, though not significant OR: 1.06; 95% CI: 0.77–1.45, p value=0.7166

For GOSE 4 or less: OR: 1.12; 95% CI=0.90– 1.38, p value=0.3138

Main findings:

• The wide variation between centres regarding PCO2 management
• ICP monitored patients had lower PCO2 levels
• PCO2 levels were lower in patients with intracranial hypertension
• No difference in mortality or 6-month neurological outcomes after propensity analysis

Comments

• Seattle international severe traumatic brain injury consensus conference (SIBICC) recommends the use of HV as second-tier therapy
• BTF guidelines recommend it only as a temporizing measure for raised ICP
• The study represents an overview of the current management of PCO2 levels in Europe
• Limitations of an observational study, with no adequately matched controls
• Wide heterogeneity in the type of injury that could impact outcomes
• The PCO2 level represents a snapshot in time; the actual levels over a longer duration may vary widely. Capnography may be a better tool to assess trends over time
• Assessment of longer-term outcomes (1 y) may be meaningful in TBI.

Our Recommendations –

There is not enough evidence to completely abandon the current practice of HV to control ICP.

However, the dogmatic practice of using HV in every single patient with severe TBI should be avoided.

Its use can be considered as a rescue measure in the setting of raised ICP, which is refractory to first-line treatment modalities.

A large RCT is needed to address this controversy further.

The post The Role of Hyperventilation in ICP Control first appeared on Critical Care Education.