All posts by Adrian Wong

ICM Experimental 1: Mechanisms of Multi-organ Failure

How to protect and resuscitate the mitochondrium: Role of Metformin and Cyclosporin

(Jean-Charles Preiser)

3 post-injury phases: Early Phase attempts to protect cellular integrity at the expense of functionality

  • changes in macro / microcirculation
  • decreased oxygen consumption
  • decreased energy expenditure
  • metabolic shutdown

Hyperlactataemia closely related to severity of sepsis; in established sepsis it is defect of oxygen utilisation, rather than impaired oxygen transport

 

Mitochondria in critical illness– more than just a powerhouse – also key roles in cell signalling (ROS), calcium homeostasis, regulation of apoptosis. Stressed mitochondria release DAMPs, further increasing inflammation and systemic toxicity

 

Metformin directly decreases mitochondrial respiration and increases aerobic glycolysis

Several studies have shown improved outcomes associated with metformin use in ITU patients

Cyclosporin A inhibits opening of mitochondrial permeability transition pore (mPTP), thereby preventing cell death

Rabbit model: cardiac arrest –> resuscitation with either 1. Control or 2. Cyclosporin A or 3. Non-immunosuppressive analogue-Inhibitor of mPTP opening –> organs harvested with functional markers recorded

 

Cyclosporin A (and non-immunosuppressive analogue-Inhibitor of mPTP opening) – protective effect on liver, kidney and heart, but not lung

Clinical:

  1. Cyclosporine before PCI for acute MI (800 pts): randomisation to bolus of Cyclosporine or Placebo –> disappointingly same primary outcome (death any cause / cardiac compromise) in both groups   ??dose ??timing-related
  2. Out-of-hospital cardiac arrest (800pts): randomisation to bolus of cyclosporine vs placebo – No difference in SOFA scores 24 hrs post-admission   ??dose ??timing-related ??inclusion criteria

 

Late and Recovery phases post-injury: Long stayers >5 days – decreased mitochondrial biogenesis, dysregulated lipid oxidation –> weakness, muscle inflammation, impaired anabolic recovery

 

Inhibitors of mitochondrial function may prevent later organ failure if given very early post-injury BUT prolonged mitochondrial dysfunction is not desirable

 

Recommended reading: Feeding mitochondria: Potential role of nutritional components to improve critical illness convalescence

 

The role of the Glucocorticoid (GC) receptor in circulatory shock

(Sabine Vettorazzi)

 

GC production and function is required for efficient response to inflammation – abnormal GC production associated with higher sepsis mortality in animal models and humans

GC binds to Glucocorticoid receptor (GR) –> translocates to nucleus

  • GR monomer –> Represses inflammation
  • GR dimer –> Induces inflammation

 

GR Dimerisation-deficient mouse model (GRdim) created, to clearly discriminate effects of GR monomers from GR dimers (which are completely absent)

Mice subjected to endotoxin-mediated shock: GRdim mice died faster than wild-type mice

  • more severe lactate acidosis
  • higher inotropic requirement for haemodynamic stability
  • impaired lung compliance
  • increased osteopontin levels (with decreased levels of anti-inflammatory IL-10)

 

GR Dimer is important for survival during LPS induced toxic shock, at least during the first 6 hours of shock in GRdim mice (only observed for 6 hours with intensive care support)

 

Why and how the heart fails

(Alain Rudiger)

 

Four shock states –

  • shock –> cardiac dysfunction, MOF
  • combination of shock states commonly occur

 

Cardiac dysfunction during Inflammatory Shock:

  • Elevated BNP and Troponin
  • Arrhythmia
  • Systolic and diastolic dysfunction

 

Is this myocardial injury the reason for cardiac dysfunction?

Little evidence of myocyte necrosis in pts dying of sepsis + impaired contractility is Reversible = functional impairment rather than structural damage

 

Adaptive myocardial depression when myocardium is at risk

  • reprogramming of genes
  • activation of fetal genes (survival program)
  • decreased energy expenditure to keep cells viable

 

Complex process of gene activation / down regulation in multiple cell-types at different times

 

Rat model 6 hours post-onset of faecal peritonitis:  500+ genes up/down regulated

  • –> downstream: signalling cascades e.g. blunted adrenergic cascade / blunted calcium transport
  • –> further downstream: affects electromechanical coupling and decreases myocardial contractility

 

Close interactions between shock, cardiac dysfunction and MOF

The heart fails as a result of multiple factors:

  • Insufficient preload
  • Excessive RV afterload
  • Arrhythmia, dyssynchrony
  • Diastolic dysfunction and impaired contractility

Lessons from Clinical Challenges in Neuro-Critical Care

Traumatic Brain Injury

Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research

Trajectories of early secondary insults correlate to outcomes of traumatic brain injury: results from a large, single centre, observational study

Clinical applications of intracranial pressure monitoring in traumatic brain injury : report of the Milan consensus conference.

 

Intracranial Haemorrhage

Definition: non-traumatic bleeding into the brain parenchyma

2nd most common type of stroke (10-30%)

5.3 million cases worldwide, 3 million deaths (2010 Global Report on Diseases)

Less than 40% of patients regain functional independence

Most important risk factors:

  • hypertension
  • anticoagulation

The critical care management of spontaneous intracranial hemorrhage: a contemporary review

Blood pressure management: BPsys < 140 -160 mmHg

  • Higher systolic pressures may lead to hematoma expansion and increased edema.
  • Prospective trials: INTERACT II, ATACH II

Correction of coagulopathy, if possible… or not?

  • Vitamin-K-antagonists (Phenprocoumon, Marcumar): Yes. Use PCC (prothrombin complex concentrate)
    •  INR-goal: < 1.3
  • DOACs: if specific antidote available and within 2-3 half lifes of substance, probably yes.
  • Heparin: use protamine.
  • Aspirin / Clopidogrel: may depend on hemorrhage size

Summary: intracranial hemorrhage

  • Data: meanwhile useful prospective works available
  • Difficult to estimate who will decompensate
  • Prognosis difficult to estimate, likely to be worse after large ICH.
    No application of score systems for single patients
  • Superficial, cortical hemorrhage: open surgery
  • Large Basal ganglia hemorrhage (> 30 ml): minimally invasive surgery
  • Intraventriular hemorrhage: EVD + Lysis (+ lumbale Drainage)
  • Decompressive surgery: trial ongoing.
  • Massive hemorrhage (> 100 ml): conservative approach
  • ICP monitoring standard in ventilated patients, optionally pbtO2, EEG, eCox, …

Subarachnoid hemorrhage

Transcranial Doppler ultrasound goal-directed therapy for the early management of severe traumatic brain injury.

Calcium antagonists for aneurysmal subarachnoid haemorrhage – Cochrane Review

Transcranial Doppler versus angiography in patients with vasospasm due to a ruptured cerebral aneurysm: A systematic review.

Hyponatraemia: Practical Management

  • Monitor volemia and Natremia after SAH
  • Fluid restriction is not recommended
  • Isotonic saline (0.9%) for drug dilution and fluids (1-3L)
  • We rarely use 3% saline (1 ml/Kg of 3% NaCl increases the PNa by 1mmol/L)
  • Consider hydrocortisone in case of vasopressor use
  • Vaptans are not useful
  • Consider urea (0.5 -1g/Kg/Day) for HypoNa + euvolemia

Summary

  • Late risk: vasospasm
  • Monitoring: depends on severity and risk of vasospasm
  • At least: TCD and ICP, PbtO2 and CMD in tissue at risk
  • HypoNa is frequent: no fluid restriction! NaCl, Steroids, Urea

Acute Management of Status Epilepticus

International League Against Epilepsy (ILAE) task force on classification

SE = Status Epilepticus

◦ condition resulting

  • from the failure of the mechanisms responsible for seizure termination
  • from the initiation of mechanisms which lead to abnormally prolonged seizures

◦Long-term consequences

  • neuronal death, neuronal injury, alteration of neuronal networks, depending on the type and duration of seizures

RSE = Refractory Status Epilepticus

  • SE that persists despite adequate administration of benzodiazepines and at least one antiepileptic drug

SRSE = Super Refractory Status Epilepticus

  • SE that continues or recurs ≥24h after onset of anaesthetic therapy, including recurrence on the reduction or withdrawal of anaesthesia.

Convulsive status epilepticus (CSE)

  • SE with convulsions / seizures / myoclonus

Non-Convulsive Status Epilepticus (NCSE)

  • SE without clinical signs à EEG diagnosis

ESICM Webinar – FOCUS on #POCUS

*This webinar was kindly sponsored by GE*

We would love to hear from you and any feedback/questions would be welcomed. OR if you want to find out more about #POCUS fellowships……

The presentation….

https://www.icloud.com/keynote/0TjTY6dm-GTqkL_YCFewLu4kA#ESICM_webinar

Reference list

What is #POCUS

Lichtenstein D, van Hooland S, Elbers P et al. Ten good reasons to practice ultrasound in critical care. 

Lichtenstein D and Mezière G (2008) Relevance of lung ultrasound in the diagnosis of acute respiratory failure. The BLUE-protocol. 

Perera P, Mailhot T, Riley D et al. The RUSH exam: Rapid ultrasound in shock in the evaluation of the critically ill. 

Lichtenstein D.A. Lung Ultrasound as the First Step of Management of a Cardiac Arrest: The SESAME-Protocol. In: Lung Ultrasound in the Critically Ill. Springer, 2016 Cham

Training in #POCUS

Malbrain MLNG, De Tavernier B, Haverals S et al. Executive summary on the use of ultrasound in the critically ill: consensus report from the 3rd Course on Acute Care Ultrasound (CACU). 

Mayo P, Beaulieu Y, Doelken P et al. American College of Chest Physicians/La Société de Réanimation de Langue Française statement on competence in critical care ultrasonography. 

Expert Round Table on Ultrasound in ICU. International expert statement on training standards for critical care ultrasonography. 

Wong A, Galarza L and Duska F. Critical Care Ultrasound: A systematic review of international training competencies and program. 

Galarza L, Wong A and Malbrain M. The state of critical care ultrasound training in Europe: A survey of trainers and a comparison of available accreditation programmes. 

Future of #POCUS

Robba C, Goffi A, Geeraerts T et al. Brain ultrasonography: methodology, basic and advanced principles and clinical application. A narrative review. 

Aitkinson P, Beckett N, French N et al. Does point-of-care ultrasound use impact resuscitation length, rates of intervention and clinical outcomes during cardiac arrest? A study from the Sonography in Hypotension and Cardiac Arrest in the Emergency Department (SHoC-ED) Investigators. 

Feng M, McSparron JI, Kien Dt et al. Transthoraccic echocardiography and mortality in sepsis: analysis of MIMIC-III database.

If you are REALLY interested in pushing the limits of ultrasonography in critical care … https://thinkingcriticalcare.com/

Recommended textbooks

TTM @ #EuAsia19

Optimal depth, timing and duration based on recent clinical trials (K Sunde)

Cardiac arrest is a complex disease

  • several different causes (many untreatable, irreversible, extreme challenging)
  • large heterogeneity
  • challenges the system due to the limited/crucial time-intervals (hypoxia/extreme ischemia)
  • large differences in quality of care within and inbetween systems (both during ALS and in post resuscitation care)
  • very high mortality

Depth and Timing

ILCOR Statement 2003 –

Unconscious adult patients with spontaneous circulation after out-of hospital cardiac arrest should be cooled to 32-34°C for 12-24 hrs when the initial rhythm was VF.

For any other rhythm, or cardiac arrest inhospital, such cooling may also be beneficial.

Outcome, timing and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest.

  • timing, speed and duration of hypothermia had no impact on outcome!

Confounding aspects regarding early/fast cooling

  • the lack of protection against a drop in core temperature is due to a larger and deeper brain injury! (link)
  • If you are really “dead” you are colder and it is very easy to cool you fast! (link)

Intra-Arrest Transnasal Evaporative Cooling: A Randomized, Prehospital, Multicenter Study (PRINCE: Pre-ROSC IntraNasal Cooling Effectiveness) link

Duration of TTM

Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest

Prolonged targeted temperature management in patients suffering from out-of-hospital cardiac arrest

Conclusion

  • Cardiac arrest is complex, with large heterogeneity and very high mortality
  • Large differences in quality of care within and inbetween systems
  • Concerning pathophysiology and TTM: depth, speed and duration impacts on the reperfusion injury/brain injury
  • We are concluding based on pragmatic trials not optimizing the intervention tested or considering the ongoing pathophysiology!
  • Outcome assessment: cognitive function/QoL years after the arrest!

Haemodynamic Management During Targeted Temperature Management (Huang CH)

Multiple reasons for haemodynamic instability post-cardiac arrest

Haemodynamic Response Correlated to Outcome – Reversible myocardial dysfunction in survivors of out-of-hospital cardiac arrest.

Cardiovascular Response & Haemodynamic Changes In Hypothermia Treatment

  • Changes in CV β-adrenoceptor (reduced response)
  • Bradycardia
  • Increase in stroke volume
  • Reduced intravascular volume during hypothermia is by 10– 35%

Lower heart rate is associated with good one-year outcome in postresuscitation patients (link)

Survivors Have Higher Mean Arterial Pressure (link)

Lowest value of DAP over the first 6 h after ICU admission for predicting unfavourable neurological outcome at 3 months (link)

Postresuscitation hemodynamics during therapeutic hypothermia after out-of-hospital cardiac arrest with ventricular fibrillation: A retrospective study

Taiwanese Protocol