Cardiovascular Resuscitation Drugs

1
Cardiovascular Resuscitation Drugs

• Craig J. Railton
• B.Sc., M.D., Ph. D., FRCP(C)
• Assistant Professor
• Department of Anesthesia and
• Perioperative Medicine

2
Outline

• Physiology
• Indications
• Drugs
• Down
• Nitroglycerin and nitroprusside
• Phentolamine
• Up
• Norepinephrine
• Epinephrine
• Dopamine
• Dobutamine
• Levosimedran
• Atropine
• Vasopressin
• Somatostatin
• Practical Advice

3
Lung Development
4
Respiratory Physiology

• Central Control
• Brainstem 4th Ventricle
• Dorsal Respiratory Group
• inspiratory drive to phrenic and intercostal
  nerves
• Ventral Respiratory Group
• inspiratory (inhibits) and expiratory
• Pontine Respiratory Group
• inhibitory
• Respiratory Rhythm Generation
• occurs independent of chemoreceptor information

5
Respiratory Physiology

• Upper Airway
• Reflexes stop breathing and close vocal cords
  while swallowing
• Can lead to laryngospasm
• Tracheobronchial/Pulmonary
• Stretch Receptors
• mechano receptors
• (Hering-Breuer Reflex)
• CPAP prevents inspiration (weak reflex in humans)
• Irritant Receptors
• Localized in carina and bronchi implicated in
  asthma,
• J-Receptors
• Cause Apnea and bronchoconstriction with respect
  to irritants

6
Respiratory Physiology

• Chemical Control
• Central Chemical Receptors
• Located ventral lateral medulla
• Respond to changes in pH of CSF
• Peripheral Receptors
• Located in carotid bodies
• Respond to changes in PaCO2 and pH
• Contribute approximately 15 to respiratory drive
• Chronic hypoxia attenuates response patient
  becomes dependent on PaC02 to breath

7
(No Transcript)
8
Cardiac Physiology

• Many changes in circulation at time of birth
• Closure of Ductus Arteriosis
• Decrease in pulmonary vascular resistance
• Over the next months to decades many changes in
  Heart rate and blood pressure

9
Cardiac Physiology
10
Cardiac Physiology

• CO Stroke Volume x Rate
• BP CO x SVR
• BP Stroke Volume x Rate x SVR

11
Autonomic Nervous System

• Two Divisions
• Parasympathetic
• Sympathetic
• Cross over of drugs
• Overlap of systems
• Gateway to resuscitation

12
(No Transcript)
13
ANS Nicotinic Acetyl Choline Receptors
14
ANS Muscarinic ACh Receptors
15
ANS Adrenergic Receptors
16
(No Transcript)
17
CVS Receptor Types
18
Receptors More Receptors!

• Alpha (2)
• Beta (2)
• Dopamine (2-5)
• Vasopressin (2-5)
• Acetyl Choline
• Ca Channels
• Angiotensin (3 metabolites)
• Cardiac Peptides
• Somatostatin

• VIP
• Adenosine/ATP
• Serotonin
• Glucagon
• Thrombin
• Histamine
• Prostaglandins
• Opiates
• Bradykinin
• Nitric oxide

19
Dosing and Side Effects
20
Indications

• Birth
• Arrest
• Sepsis
• Overdose
• Trauma
• Severe Illness
• Status Situations

21
Down Drugs

• Nitric Oxide
• Nitroglycerin
• Nitroprusside
• Phentolamine
• Phenoxybenzamine

22
Nitric Oxide

• Endothelium Derived Releasing Factor
• Recognized as nitric oxide (NO) in 1987
• Nobel Prize awarded for research (Moncada Nature
  1987 327524.)
• Derived from Arginine
• Multiple body systems
• Increases intracellular cGMP
• Half-life 5 seconds
• Inactivated by hemoglobin
• Physiologic effects dictated by NO synthase
  location

23
Nitric Oxide Mechanism
24
Nitric Oxide

• CVS
• SVR (NO is usual major player)
• NO determines distribution of Cardiac Output
  (lung and brain especially)
• NO synthesis increases due to hypoxia
• NO is a negative inotrope and chronotrope
• Arteries make more NO than do veins
• Lung
• NO improves oxygenation in ARDS
• Inhaled NO distributed by ventilation not
  vascular flow
• NO opposes pulmonary responses to metabolites
  that increase PVR
• Metabolites of NO (NO2) are lung toxic

25
Nitric Oxide

• Platelets
• NO inhibits aggregation
• Immune
• NO sythesis can be triggered by immune system
• NO is toxic to microorganisms
• NO modulates inflammation
• CNS
• NO is involved in excitatory neurotransmission
• NO synthase inhibition decreases NMDA mediated
  neurotransmission
• NO synthase inhibitors cause a dose related
  response in MAC

26
Nitroglycerin - NTG

• Explosive
• Industrial Chemical A. Nobel
• Releases NO in body
• Medical uses
• Angina pectoris
• Hypertensive Crisis
• Uterine tone reduction
• Erections in ED? (Durex CSD500)
• Spider bites?
• Veins gtgt Arteries
• Half-life 1.5 minutes

27
Nitroglycerin - NTG

• Advantages
• Fast on/off
• Coronary vasodilation
• Decreased preload
• Decrease Cardiac Wall Tension
• Multiple Administration Routes
• IV, SL, transdermal
• Useful for XC induced HTN

• Disadvantages
• Methemoglobin production
• Decreased sensitivity after a few hours
• Hypotension
• Headache
• Glass IV bottles must be used
• Fe (needles) catalyzes breakdown

28
Nitroprusside - SNP

• Source of NO
• Reacts with hemoglobin releasing NO
• Indirect Acting
• Primarily affects arteries and veins
• Useful in hypertensive crisis
• Useful in XC induced HTN

29
Nitroprusside - SNP

• Advantages
• Arteries and Veins
• No effect on non-vascular smooth muscle (contrast
  NTG)
• Fast onset
• potent

• Disadvantages
• Methemoglobin formation
• Cyanide production if infusion rate gt2 m/kg per
  min
• Thiocyanate toxicity
• Light Sensitive (decomposition to HCN)
• Use D5W and wrap with aluminium foil
• Ok to use for 24 h
• Tachyphylaxsis
• Avoid in pregnancy (cyanide)
• Can worsen oxyenation

30
Methemoglobinemia

• SNP reaction with Hgb produces methemoglobin
• Clinically significant methemoglobinemia is not
  usually a problem
• Dosing over 10 mg/kg is needed to produce 10
  methemoglobin
• Methemoglobinemia should be considered if poor
  oxygenation (Co-oximitry)
• Treatment
• Methylene Blue 1-2 mg/kg
• May be repeated with caution
• Can produce paradoxical methemoglobinemia
• Isosufan Blue Dye (sentinal node) can interfere
  with co-oximiety

31
Cyanide Toxicity

• Not usually a problem with SNP
• Methemoglobin and Liver can remove CN if infusion
  rate lt 2m/kg min
• Maximum infusion rates can only be used for about
  10 minutes
• If Suphydryl donors and methemoglobin are
  consumed CN toxicity can occur
• CN binds tissue cytochromes
• High mixed venous PO2 in the presence of acidosis
  and plasma lactate gt10 mmol
• Treatment
• Correct metabolic acidosis (NaHCO3)
• NaS2O3 (Sodium Thiosulphate) 150 mg/kg over 15
  minutes
• If hemodynamics deteriorating use Sodium Nitrate
  5 mg/kg
• Converts Hgb to metHgb to remove CN
• Hydroxycobalmin (vit B12) 25 mg/h to max of 100
  mg

32
Thiocyanate Toxicity

• SCN is byproduct of CN metabolism
• SCN is slowly cleared by kidney
• Rare
• Prolonged infusion (3 to 14 days) at maximum
  rates of SNP are needed
• Renal failure increases risk
• Clinical Signs
• Hyper-reflexia, nausea, vomiting, confusion,
  psychosis, miosis, seizures, coma
• Treatment
• Dialysis

33
Phentolamine

• Reversible alpha blocker
• Useful for pheos and cocaine overdose
• Not commonly used
• Used to help diagnose CRP II

34
Phenoxybenzamine

• Advantages
• Effective
• Can be used where beta-blockers, CaCB and
  nitrates not effective
• reversible

• Disadvantages
• Pharmacy PITB factor
• Must be mixed
• Must be run as infusion
• Profound hypotension possible

35
Phenoxybenzamine

• Irreversible alpha blocker
• Available from Health Canada
• Used to alpha block pheochromocytoma patients
• Not available at pharmacies

36
Others

• Isorbide dinitrate (oral nitrate)
• Hydralazine (alpha blocker)
• Dipyridamole (angina cardiac vasodilator)
• Papaverine (opiate vasodilator)
• Trimethaphan (not really used)
• Dioxide (used in renal induced HTN)
• CaCB
• Beta-blockers

37
UP Drugs

• Norepinephrine
• Epinephrine
• Dopamine
• Dobutamine
• Levosimedran
• Atropine
• Vasopressin
• Somatostatin

38
ABC

• Airway
• Help
• RT
• Anesthesia
• Breathing
• Proper Equipment
• Laerdal Bag only way to deliver 100 O2
• Circulation

39
Oxygen

• Essential to life
• Oxygen and CO2 are linked
• Alveolar Gas Equation
• PAO2 FIO2 (PB-PH2O)- PaCO2/RQ

40
O2 and CO2
41
pH

• Control of physiologic pH is important!
• Receptor binding is strongly affected by pH
• Oxygen delivery affected by pH (Haldane effect)
• Using respiratory function to your advantage is
  beneficial
• In general, hearts prefer a higher physiologic pH
• Acidosis makes resuscitation more difficult

42
IV Fluids

• D5W, D10W, 2/3 1/3 have no place in
  resuscitation
• T1/2 12-15 min no residual intravascular
  volume increase
• BJA 2001, 87(6), 834.
• Ringers Lactate, NS should be first choices
• T1/2 30 60 min approx. 1/3 remains
  intervascular
• BJA 2001, 87(3), 406.
• Consider colloids for longer effect
• T1/2 12 hours
• Blood products in Trauma or Active Bleeding

43
Electrolytes

• Calcium
• Goal is to restore to normal values
• Magnesium and Calcium are partners

44
Effect of Preload
45
Catecholamines

• All drugs in this class have similar chemical
  structure
• Cross reactivity to receptors

46
Mechanism G Proteins
47
Norepinephrine (Levophed)

• Produced in Neurons
• Precursor to EPI
• a and b receptors
• T1/2 lt 1 minute
• Very potent

48
Norepinephrine

• Advantages
• Direct agonist
• Physiologic
• Predictable
• Potent
• Improves splanchnic blood flow
• Best?
• Crit Care Med 2000 282758.

• Disadvantages
• Usually overdosed (5-10x needed)
• Higher doses limit usefulness (increased SVR)
• May be bad in ischemic heart
• Invasive monitoring of fluid status required
• Central line needed

49
Epinephrine

• Most widely used catechol
• Receptor effect depends on location in body
• a (central and skin) in some b (perhiperal)
• T1/2 lt 1 minute

50
Epinephrine

• Advantages
• mixed effect is often desired
• b effects dominate at low concentrations
• Renal blood flow preserved

• Disadvantages
• Unpredictable
• Easily overdosed
• Induces dysrhythmias
• Central lines needed
• BP monitoring

51
Dopamine

• Peripheral a receptors
• Dopamine receptors in some vessels (kidney)
• Renal protection is a myth
• Some direct action
• T1/2 lt 1 minute

52
Dopamine

• Advantages
• Effects all three adreno receptors
• DAgt b gt a
• Easier to use

• Disadvantages
• No renal protection
• Auton Pharmacol 1990, 10123.
• High doses needed for BP improvement
• SVR increase overrides cardiac effects
• Great inter individual response to drug
• Not best drug for septic shock

53
Dopamine

• Renal Dose Dopamine is a myth
• Intravascular volume is the key
• Review Curr Opin Crit Care 2003, 9(6)481.
• J Am Soc Nephrol 2001, 12(supp 17)S33.
• Curr Opin Nephrol Hypertens 2000, 9501.
• Jam Am Soc Nephrol 2003, 14792.
• BMJ 1998, 316 961.
• Crit Care Med 2001, 291526. (meta analysis)

54
Dobutamine

• Synthetic catechol
• Non selective b agonist
• Decreases SVR
• Improves CO (inotropic effect)
• T1/2 2 minutes

55
Dobutamine

• Advantages
• b agonist
• Increases HR
• Increases inotropy
• Decreases SVR

• Disadvantages
• Increases myocardial Oxygen demand
• Proarrhythmagenic
• Rare tachyphalaxis
• Monitoring very useful

56
DA vs. DBT - Arterial
57
DA vs. DBT - Venous
58
Levosimendan

• New
• Ca Sensitizer
• Used in Heart Failure
• Trade Name Simdax (Abbott)
• Increases cardiac contractility
• Causes Vasodilation

59
Levosimendan

• Advantages
• New
• Myofilament Ca Sensitizer
• Some PDE III actions
• similar to dobutamine
• No advantage over dobuta
• SURVIVE Trial in JAMA 2007 297(17)1883.
• No better than dobutamine in CHF
• Abott may not develop further
• Not Health Canada Approved

• Disadvantages
• New
• Contraindications
• Renal impairment
• Hepatic impairment
• Hypotension
• Tachycardia
• Torsades de Points
• Hypotension
• Arrhythmias (VT, torsades)
• Hypokalemia
• Myocardial ishcemia

60
Atropine

• Muscarinic Antagonist
• Can augment a and b agonists
• Multiple tissue effects
• Useful in children CO depends on rate
• Differential effects in tissues
• Effects can be overcome by sufficient amounts of
  ACh
• Penetrates CNS
• Overdose can be fatal
• Useful in Cholinergic poisonings

61
Vasopressin

• Naturally occuring hormone
• Prohormone made in hypothalamus
• Made in pituitary and some neurons
• Also known as Arginine Vasopressin (AVP) and
  anti-diuretic hormone (ADH)
• Very short half life
• Effects are small if healthy
• More profound effects in shock states

62
Vasopressin

• Advantages
• Uses non SNS pathway
• Helps augment other pressors
• Helps improve release of ACTH and CRH
• Possibly better than epinephrine at Cardiac
  Arrest

• Disadvantages
• Water retention
• Hyponatremia (mild to severe)
• Iatrogenic Diabetes insipidus?

63
Somatostatin

• Octreotide (synthetic derivatiive)
• Growth Hormone Inhibiting Peptide
• Produce in GI system
• Stomach, intestine, delta cell pancreas
• Inhibits release of multiple peptides gastrin,
  CCK, glucagon, growth hormone, insulin, secretin,
  vasoactive intestinal peptide, TSH, and
  pancreatic polypeptide
• Alters splancnic blood flow

64
Somatostatin

• Advantages
• Useful for carcinod and VIP tumors
• Useful in GI bleed situations esp. gastric
  varaces
• Can be given TID (octreotide) or by infusion
  (both)
• useful in sulfonyl urea overdose to treat
  hypoglycemia
• Used to treat diarhea

• Disadvantages
• Cost
• Nausea and vomiting
• Reduces GI blood flow and fluid secretion
• constipation

65
Hemodynamics
66
Others

• Phenylepherine
• Ephedrine
• Isoproterenol
• Nitric Oxide
• Digitalis
• Glucagon (beta-blocker overdose)
• Lucitropes (phosphodiesterase inhibitors)
• Milrinone
• Aminrone
• Enoximone
• Piroximone
• Theophylline
• Caffine

67
Time

• Normal BP needs to be restored quickly
• Patients will usually tolerate about 1 hour of
  hypotension with minor metabolic problems
• Hypotension longer than 1 hour increases
  likelihood of bad outcomes

68
Practical Advise

• How do you make up pressors?
• How do you start them initially?
• 2 amps in 250 ml of D5W or NS
• start at 10 ml/h
• Titrate rate to effect
• The correct dose is the dose that produces the
  clinical effect you desire