Short summary

Single center randomized trial with allocation of 80 comatose out-of-hospital cardiac arrest patients undergoing temperature target management, to normal or high blood pressure target during post resuscitation care. Secondary a descriptive prospective cohort study, measuring lactate to pyruvate (LP) ratio obtained by microdialysis (MD) of the cerebral venous outflow, during the peri-cardiac arrest period. The study aim to (I) investigate whether the LP ratio obtained by MD of the cerebral venous outflow reflects a derangement of global cerebral energy state during the peri-cardiac arrest period and (II) investigate the correlation between LP ratio and neurological outcome among patients with cardiac arrest and (III) investigate the correlation between LP ratio and the randomized blood pressure targets.

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Rationale

In comatose patients resuscitated from out of hospital cardiac arrest (OHCA), neurological injuries remain the leading cause of death. The in-hospital mortality is reported at 30-50%, and the total mortality, although improved substantially over the last decade; remain to be significant, in most countries at up to 90%. The brain of a patient resuscitated after cardiac arrest (CA) may have suffered ischemia and when spontaneous circulation is re-established, the subsequent reperfusion may cause further damage. Brain ischemia and the reperfusion injury lead to tissue degeneration and loss of neurological function, the extent dependent on duration and density of the insult. Temperature control and Targeted Temperature Management (TTM) targeting 33-36°C may mitigate this damage and is recommended in current international guidelines. However, managing post cardiac arrest patients are much more complicated than TTM alone, and blood pressure measurements and mechanical ventilation as part of post resuscitation care is emphasized. An adequate blood pressure must be maintained in the post-cardiac arrest patient. Episodes of hypotension can cause secondary injury, in addition to any initial insult incurred during the arrest by the brain and other organs. Mean arterial blood pressure (MAP) should be above 65 mmHg to reverse the acute shock state, and may preferably 80 to 100 mmHg to optimize cerebral perfusion. When determining blood pressure goals, clinicians must balance the metabolic needs of an ischemic brain with the potential for overstressing a decompensated heart. Cerebral autoregulation is often impaired after cardiac arrest and brain perfusion declines when the MAP falls below 80 to 100 mmHg. However, if the MAP is adequate, regional cerebral perfusion matches metabolic activity, according to positron emission tomography (PET) studies in post-cardiac arrest patients. Thus, maintaining an adequate MAP helps to avoid further brain injury. However, blood pressure goals have not been investigated in prospective clinical trials, and remain to be based on observational data and extrapolation from experimental data. While experimental studies suggest that high mean blood pressure targets are needed for maintaining cerebral blood flow, registries on consecutive clinical cases undergoing post resuscitation care suggest that lower blood pressure targets are used in clinical practice. But data RCT´s addressing specific targets in post resuscitation care have not been performed. The current trial addresses these strategies for neuroprotection in using design of two different target blood pressure levels. Intervention: 1:1 randomization:

"Normal MAP" (approximately 65 mmHg) vs. "high MAP" (approximately 75 mmHg)

Markers measuring global cerebral ischemia caused by cardiac arrest and consecutive resuscitation, and reflecting the metabolic changes after successful resuscitation are urgently needed to enable a more personalized resuscitation and post resuscitation care.

It is technically simple and feasible to place a microdialysis catheter in the jugular bulb and monitor biochemical variables related to cerebral energy metabolism bedside. The LP ratio obtained from microdialysis of cerebral venous blood may be a sensitive indicator of impending cerebral damage and might play a critical role in detecting the early responses of post resuscitation care. Aim of this study is to investigate the global cerebral metabolic changes during CA and post-resuscitation care. 

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Description of the cohort

Single center randomized trial with allocation of 80 comatose out-of-hospital cardiac arrest patients undergoing TTM, to normal or high blood pressure target during ICU stay.

Inclusion criteria: 18 years or older, out-of-hospital cardiac arrest (OHCA) of presumed cardiac cause, unconsciousness (Glasgow Coma Score 8 or lower) after sustained return of spontaneous circulation (ROSC) (20 minutes of circulation), target temperature management is indicated.

Exclusion criteria: Conscious patients, pregnancy, OHCA of presumed non-cardiac cause, cardiac arrest after arrival in hospital, known bleeding diathesis, suspected or confirmed acute intracranial bleeding, suspected or confirmed acute stroke, temperature on admission <30°C, unwitnessed asystole, persistent cardiogenic shock, known limitations in therapy, known disease making 180 day survival unlikely, known pre-arrest cerebral performance category 3 or 4, > 240 minutes from ROSC to randomization. 

Data and biological material

Primary outcome: Analysis will compare the two target blood pressure groups with respect to LP ratio.

Secondary outcomes: Cerebral Performance Category (CPC) when discharged from hospital, time to death, daily cumulated vasopressor requirement during ICU stay and need for combination of vasopressors and inotropic agents or mechanical circulatory support. All end-points are correlated to the randomized blood pressure groups.

Method: Interventions are considered emergency procedures and study blood pressure measurement using the study blood pressure modules should be commenced as soon as possible after sustained ROSC, screening and randomisation. Study target blood pressure will be blinded. Patients will be mechanically ventilated, sedated (propofol/fentanyl) and when necessary paralysed with neuromuscular blocking agents to reduce shivering and subsequent heat-generation and energy consumption. The core body temperature will be set as quickly as possible at the predefined target temperature, according to intervention allocation, with 4°C intravenous solutions, and commercially available cooling devices at the discretion of the treating physician. The target core temperature is then maintained for 24 h. After the maintenance period core temperature is gradually raised to normothermia of 37°C with a rewarming rate of no more than 0.5°C/hour. Body temperature is then maintained at normothermia 37 ±0.5°C for as long the as patient is comatose until 72 hours from sustained ROSC in treatment groups, using pharmacological treatment and temperature management systems when applicable. 

The study is targeting low-normal paO2 of 9.5 kPa during TTM and when mechanical ventilation is needed. The target PaO2 is reached by adjusting FiO2 and PEEP on the ventilator as long as the patient in on controlled ventilation. Patients ventilation is adjusted, targeting normocapnia of paCO2 of 4,5 - 6,0 in all patients. Serial arterial blood gas analyses will be performed open label using the commercially available equipment adjusted to 37 °C (alpha-stat).

MD catheter (CMA 67, MDialysis AB, Stockholm, Sweden) is placed in a retrograde direction into the jugular bulb. A second identical MD catheter is inserted into one brachial artery. Both catheters are inserted through a peripheral intravenous 17 GA cannula using ultrasound guidance. The positioning of the catheter in the jugular bulb above the inlet of the common facial vein is verified on lateral neck radiograph according to accepted principles. MD catheters are perfused by MD pumps (CMA 106, MDialysis AB, Stockholm, Sweden) at 0.3 UL/min. The perfusates are collected in microvials and analyzed every one hour for 72 hours by enzymatic photometric techniques and displayed bedside (Iscus, Mdialysis AB, Stockholm, Sweden). The analyses include the variables routinely monitored during intracerebral microdialysis: glucose, pyruvate, lactate, glutamate and glycerol.

Neurological status, according to the CPC-scale, and survival are evaluated every day in the intensive care unit and/or at day 1, 2, 3, 4, 5, 6, 7 and at hospital (including local hospital) discharge, whichever comes first.

Collaborating researchers and departments

Department of Anesthesiology and Intensive Care, Odense University Hospital

• Professor Palle Toft, MD, PhD, DMSc
• Consultant Anesthesiologist Henrik Schmidt, MD, PhD

Department of Neurosurgery, Odense University Hospital

• Consultant Troels Halfeld Nielsen, MD, PhD