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Influence of Morphine or Ketamine or Saline Applied During In-hospital Cardiopulmonary Resuscitation on Early Survival

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ClinicalTrials.gov Identifier: NCT04009759
Recruitment Status : Not yet recruiting
First Posted : July 5, 2019
Last Update Posted : June 11, 2021
Sponsor:
Information provided by (Responsible Party):
Vladimir Kuklin, University Hospital, Akershus

Brief Summary:
A small numbers of patients (10-15%) treated with cardiopulmonary resuscitation (CPR) are discharged from hospitals with a favorable neurologic outcome. However, a higher incidence of chest injuries (30-70%), mainly rib and sternum fractures, are observed among the survivors. It's no surprise that 6 months after cardiac arrest (CA) 50-70% of the patients who have survived continue to have pain and stress-related problems. Based on the need for the pain/stress treatment in these patients and several experimental evidences demonstrating neuroprotective features of anesthetics it is logical to presume that application of anesthesia during CPR may be indicated. In rodents exposed to hypoxic gas (5% 02, 95% N2) for 70 min, all seven animals died at the end of the experiments in the naloxone pre-treated group while only one out of seven rats died in the morphine pre-treated group, and five of seven rats died in the control group. In human volunteers, intravenously administered 60 mg of morphine did not alter cerebral blood flow and cerebral vascular resistance but markedly depressed cerebral oxygen uptake. Interestingly, in critical patients, morphine even in low doses is effective in relieving dyspnea by altering central perception and decreasing anxiety. In rats, morphine demonstrates dose- depending reduction of cerebral glucose utilization in limbic and forebrain regions. Thus, the main points of application for morphine in treatment of CA may be a reduction of oxygen/glucose consumption. Pre-treatment of zebrafish with ketamine protects against cardiac arrest-induced brain injury by inhibiting Ca2+ wave propagation and consequently it improves survival rate. Inhibition of NMDA receptors by ketamine reduces neuronal apoptosis and attenuates the systemic inflammatory response to tissue injury. The sympathomimetic effects of ketamine may facilitates recovery of systemic blood pressure during CPR. Retrospective investigations demonstrate that patients who are treated with opioids before or during CA have a statistically significantly higher survival rate and much better neurological outcome compared to untreated patients. Experimental studies have a limitation as all animals are treated with anesthesia and therefore survival rate varies between 50-90%. Thus, prospective research is urgently needed to investigate the influence of morphine or/and ketamine on survival and neurological outcome in patients with CA.

Condition or disease Intervention/treatment Phase
Cardiac Arrest Drug: Morphine Drug: Ketamine Injectable Solution Drug: Saline 0.9% Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 240 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 240 adult patients with an in-hospital cardiac arrest will be evaluated by anesthesiologist on duty for inclusions criteria to the study and randomized to get the blinded study medicine as addition to the standard treatment of cardiac arrest.
Masking: Single (Outcomes Assessor)
Masking Description: Acute bag for cardiopulmonary resuscitation (CPR) will have a trial pack containing 3 blinded ampules that will be labelled with only randomisation number. Anaesthesiologists and nurses performing CPR and research treatment will not know the content of the ampules as well as a meaning of the randomisation number. Neurologist, who will not be aware of treatment assignments, will assess neurological outcomes in all survived patients. Statistician, who will not be aware of treatment assignments, will assess statistical data in all included patients. An independent Data Monitoring Committee will assess the progress, safety data (death, long-term hospitalization, and disability) and, critical efficacy endpoints of the clinical study (survival at 1, 2, 3 and 28 days in patients after in-hospital CA) in all included patients.
Primary Purpose: Treatment
Official Title: Randomized Triple-blind Placebo Controlled Trial of Influence of Morphine or Ketamine or Saline Applied During In-hospital Cardiopulmonary Resuscitation on Early Survival and Neurological Outcome
Estimated Study Start Date : October 1, 2021
Estimated Primary Completion Date : January 1, 2025
Estimated Study Completion Date : January 1, 2026

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Morphine
Morphine group (M) (n=80), where patients will be treated with i.v. injection of Morphine 2 mg/ml - 5 ml - 10 mg "Epidural". The treatment will be given during CPR as soon as possible.
Drug: Morphine
Adult patients with an in-hospital cardiac arrest will be evaluated by anaesthesiologists for inclusions criteria to the study and randomised to get the blinded study medicine as addition to standard treatment of cardiac arrest. Randomization will be performed by means of sealed envelopes containing number of syringe that will be used.

Active Comparator: Ketamine
Ketamine (K) group (n=80), where patients will be treated with i.v. injection of S-Ketamine 10 mg/ml - 5 ml - 50 mg "Ketamin Abcur". The treatment will be given during CPR as soon as possible.
Drug: Ketamine Injectable Solution
Adult patients with an in-hospital cardiac arrest will be evaluated by anaesthesiologists for inclusions criteria to the study and randomised to get the blinded study medicine as addition to standard treatment of cardiac arrest. Randomization will be performed by means of sealed envelopes containing number of syringe that will be used.
Other Name: Ketamine

Placebo Comparator: Saline
Control group (n=80), where patients will be treated with i.v. 5 ml of NaCl 0,9% "B. Braun". The treatment will be given during CPR as soon as possible.
Drug: Saline 0.9%
Adult patients with an in-hospital cardiac arrest will be evaluated by anaesthesiologists for inclusions criteria to the study and randomised to get the blinded study medicine as addition to standard treatment of cardiac arrest. Randomization will be performed by means of sealed envelopes containing number of syringe that will be used.
Other Name: Saline




Primary Outcome Measures :
  1. Survival at 28 days in patients after in-hospital cardiac arrest [ Time Frame: 28th day ]
    Survival rate at 28 days in patients after in-hospital cardiac arrest treated or not with Morphine or ketamine during CPR


Secondary Outcome Measures :
  1. Measurement of biochemical markers of brain damage (NSE, S-100B protein) [ Time Frame: 2,12, 24 and 48 hours ]
    Measurement of biochemical markers of brain damage (NSE, S-100B protein) at 2,12, 24 and 48 hours in patients after out-of-hospital cardiac arrest.

  2. Length of stay in the intensive care unit [ Time Frame: 3 month ]
    Registration of length of patients stay (days) in the intensive care units

  3. Length of stay in the hospital [ Time Frame: 3 months ]
    Registration of patients stay (days) in the hospitals

  4. Survival rate at 3 months after cardiac arrest [ Time Frame: 3 months ]
    Registration of survival rate at 3 months after cardiac arrest

  5. Neurological outcome at the hospital discharge [ Time Frame: 6 months ]

    Modified Rankin Scale (mRS) will be used for evaluation of neurological outcome. The mRS-9Q Survey and web calculator / error-checker can be accessed freely at:

    www.modifiedrankin.com. The mRS score encodes meaningful levels of function from no symptoms or functional impairment (mRS score = 0) through to severe disability requiring constant nursing care (mRS score = 5). the mRS-9Q is an easy-to-use tool to determine the mRS score with very good interobserver reliability and reproducibility. Web-based calculator can be also administered by personnel without clinical training, either in person or by telephone.


  6. neurological outcome at 3 months after cardiac arrest [ Time Frame: 3 months ]

    Modified Rankin Scale (mRS) will be used for evaluation of neurological outcome. The mRS-9Q Survey and web calculator / error-checker can be accessed freely at:

    www.modifiedrankin.com. The mRS score encodes meaningful levels of function from no symptoms or functional impairment (mRS score = 0) through to severe disability requiring constant nursing care (mRS score = 5). the mRS-9Q is an easy-to-use tool to determine the mRS score with very good interobserver reliability and reproducibility. Web-based calculator can be also administered by personnel without clinical training, either in person or by telephone.




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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

- All adult patients with in-hospital cardiac arrest

Exclusion Criteria:

  • an age of less than 18 years
  • drugs poisoning or the administration of opioids or Ketamine 24 hours before the cardiac arrest
  • terminal phase of oncological or other chronic diseases
  • poor communication and physical capabilities due to psychiatric or neurological diseases
  • dementia or Alzheimers
  • extremely reduced weight or physical ability and activity
  • known history of chronic use of opioids/Ketamine

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04009759


Contacts
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Contact: Vladimir Kuklin, dr med +4798838024 vkuklin@me.com
Contact: Lisa Dybvik, cand med +4746669271 ldybvik@hotmail.com

Sponsors and Collaborators
University Hospital, Akershus
Additional Information:
Publications:

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Responsible Party: Vladimir Kuklin, Head of day case surgery unit, University Hospital, Akershus
ClinicalTrials.gov Identifier: NCT04009759    
Other Study ID Numbers: Akershus university hospital
First Posted: July 5, 2019    Key Record Dates
Last Update Posted: June 11, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Vladimir Kuklin, University Hospital, Akershus:
cardiac arrest
Morphine
Ketamine
Survival rate
Additional relevant MeSH terms:
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Heart Arrest
Heart Diseases
Cardiovascular Diseases
Morphine
Ketamine
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anesthetics, Dissociative
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action