Septic Shock Therapy: A Guide

Basic Pharmacology of Emergencies

Basic Therapy of Septic Shock

• Oxygen is used to maintain SpO2 between 90-96%.
• Venous access and initial investigations, such as lactate and procalcitonin levels, are crucial.
• Obtain microbiologic samples and imaging studies.
• Perform aggressive fluid resuscitation.
• Administer empiric broad-spectrum antibiotics within 1 hour.
• Admit the patient to the ICU.
• Vasopressors are used if the patient doesn't respond to initial therapy.
• Additional therapies include, GCS, Inotropic drugs, and RBC transfusions.
• Supportive measures include nutrition, stress ulcer prophylaxis, thromboembolism prophylaxis, intensive insulin therapy, external cooling/antipyretic therapy, and mechanical ventilation if needed using neuromuscular blocking agents.

Aggressive Fluid Resuscitation

• Administer 30ml/kg of fluids within the first 3 hours.
• Rapid infusions of 500 ml boluses are recommended.
• Avoid gelatins like HES and pentastarch due to kidney hazards.
• Use balanced crystalloids.

Empiric Antimicrobial Therapy

• Administer antimicrobials within the first hour.
• Base treatment on initial history, tests, examination, and imaging, tailoring it to each individual.
• Implement source control via surgery or catheter removal.
• Use broad-spectrum antibiotics.
• Common pathogens include E. coli, Staphylococcus Aureus (MRSA), K. Pneumoniae, and Streptococcus Pneumoniae.

Antimicrobial Therapy Practice

• When Pseudomonas is unlikely, use Vancomycin plus either a third-generation cephalosporin (Ceftriaxone, Cefotaxime), a β-lactam/β-lactamase inhibitor (Piperacillin/Tazobactam), or a carbapenem (Imipenem, Meropenem).
• When Pseudomonas is likely, use Vancomycin plus an antipseudomonal cephalosporin (Ceftazidime, Cefepime), an antipseudomonal β-lactam/β-lactamase inhibitor (Piperacillin/Tazobactam), an antipseudomonal carbapenem (Imipenem, Meropenem), a fluoroquinolone (Ciprofloxacin), an aminoglycoside (gentamycin, Amikacin), or monobactam (Aztreonam).
• If Candida or Aspergillus is suspected, use Echinocandin - Caspofungin for Candida or Voriconazole for Aspergillus.
• Dosing should be maximal and use a full "high-end" dose with a loading dose, if possible.

Septic Shock: Vasopressors

• Norepinephrine
• Adrenaline (+/-)
• Dopamine
• Dobutamine
• Vasopressines (Terlipressin)

Cardiac Arrest and Reanimation

• Ventricular fibrillation accounts for 90% of cardiac arrests.
• Defibrillation is the best treatment.
• Follow the instructions of the AED.
• Electrodes serve a dual purpose of monitoring heart electrical activity and delivering shock through contacts.
• Attach one electrode under the right collar bone.
• Attach the other electrode below and to the left of the left nipple in the midaxillary line.

Cardiopulmonary Resuscitation: Adult Basic Life Support

• Check for responsiveness.
• Open the airway.
• Check for breathing.
• Breathe for the patient.
• Assess circulation for 10 seconds.
• If no circulation, compress the chest at a rate of 100 per minute.
• Continue rescue breathing and check circulation every 2 minutes.

Resuscitation Drugs (VF): Adrenaline

• Adrenaline increases heart rate via β1 receptors, dilates bronchi via β2 receptors, and constricts vessels via α1 receptors.
• The dose affects the intensity of these responses.
• α1 receptor Agonist = A = NA
• α2 receptor Agonist = A > NA
• β1 receptor Agonist = NA > A
• β2 receptor Agonist = A > NA
• β3 receptor Agonist = NA > A
• Administer 1.0 mg of adrenaline intravenously after the third defibrillation, then every 3-5 minutes.
• Stimulates the sinoatrial node (SAN) and has an inotropic action.
• Adrenaline increases peripheral resistance and diastolic pressure, therefore also increasing coronary and cerebral blood flow.
• Adrenaline may increase oxygen consumption and has proarrhythmic activity.
• Can cause Aa-vv bypass in the lungs leading to hypoxemia and disturbs microcirculation.

Adrenaline Dosage

• For CPR, administer 1mg every 3-5 minutes intravenously or intraosseously.
• Children should receive 10-30 µg/kg.
• For Bradycardia, administer 2-10 µg/min.
• For Asthma, administer 0.3 mg subcutaneously.
• For Anaphylaxis:
  • Administer 0.5 mg intramuscularly or intracutaneously.
  • Newborns (< 6 months) receive 150 µg.
  • Children (6 months – 6 years) receive 150 µg.
  • Children (6 - 12 years) receive 300 µg.
  • If older than 12 years administer 0.5 mg.

Resuscitation Drugs: Amiodarone

• Amiodarone blocks VOC Channels K+.
• Administer 300 mg intravenously after the 3rd defibrillation.
• Administer 150 mg if ventricular tachycardia/ventricular fibrillation (VT/VF) persists.
• It is not recommended in pulseless electrical activity/asystole (PEA/asystole).

Resuscitation Drugs: Lidocaine

• Lidocaine is used in case of lack of amiodarone or known allergy to amiodarone.
• Lidocaine reduces inactivated Na+ channels, decreasing Vmax if it was increased.
• It also decreases duration of refraction and probability of afterdepolarization.
• Lidocaine is for severe Ventricular Arrhythmia (VA) after Acute Myocardial Infarction (AMI), specifically IV/V Lown classification.
• It is used in VF (Resuscitation) when there is low voltage VF →A→ high voltage VF.
• It addresses Ventricular dysrhythmias caused by Digitalis.
• Lidocaine is administered only parenterally due to its strong first-pass effect.
• A bolus of 100 mg - 1-1.5/kg + bolus 50 mg (max. 3mg/kg) is needed.

Reanimation Drugs

• Sodium Bicarbonate(NaHCO3) should be used at a dose of 1 mmol/kg (50 mmol) but only after lack of effect of defibrillation, BLS, intubation, and adrenaline.
• It is useful in cardiac arrest with hyperkalemia, intoxication with antidepressants and it neutralizes metabolic acidosis.
• Sodium Bicarbonate may cause severe tissue alkalosis, introduce an important sodium load with plasma hyperosmolarity, causes a left shift of the oxygen binding curve, liberates CO2 leading to paradoxical respiratory and intracellular acidosis with Inotropic negative effect.

Reanimation Drugs: VF

• Calcium salts can be given at 2-4 mg/kg (10 ml 10% CaCl2).
• This helps with contractility and is indicated in patients with hyperkalemia or hypocalcemia.
• But calcium may stop heart contraction (stone heart), especially in patients with acidosis and treated with digitalis and is not recommended in defibrillative rhythms.
• Magnesium salts: 2g; repeated after 10-15 min in VT; SVT; TdP and used for digitalis intoxication with hipomagnesemia.
• Magnesium salts help with Ach releases, improves contractile reaction of stunned heart, minimize infarct area but poses a risk of hypotonia.
• Noradrenaline and Dopamine are vasopressors used after successful circulatory rescue to maintain higher blood pressure, infusion is recommended.
• Noradrenaline acts on Vessels via α1 ↑ and Heart via β1 ↑.
• Dopamine acts on Kidney via D↑, Heart via β1↑ and Vessels via α1↑.

Other Reanimation Drugs

• Atropine 0.5 – 1 mg (max. 3 mg) after successful circulatory rescue to prevent bradycardia and maintain BP
• Lidocaine 1 mg/kg bolus than 1-4 mg/min, be mindful about the negative inotropic effect.
• Fluids: Crystalloid/colloid with the exclusion of glucose due to risk of cerebral swelling

Reanimation Drugs: Asystole

• Adrenaline
• Think over NaHCO3
• Caused by severe heart ischemia – bad prognosis

Reanimation Drugs: Electromechanical Dissociation (PEA)

• Adrenaline

Fluids

• If hypovolemia is suspected, use crystalloids/colloids
• Glucose is not recommended, it’s neurotoxic.

Thrombolytics

• Tenecteplase 500 ug/kg iv bolus
• Alteplase 10 mg / 10 min iv than infusion 90 mg/2h
• Only if you suspect pulmonary thrombosis.
• CPR should be continued by 60-90 min.

Cardiac Arrest

• Conditions that merit special attention.

Hyperkalemia

• Mild: 5.9 mmol/L
  • Use IV fluids (0.9% NaCl).
  • Calcium resonium or polystyrene sulfonate to take effect after 1 - 3 hours, max of 6 hours.
  • Furosemide
• Moderate: 6.4 mmol/L
  • IV fluids
  • Glucose 25g + Insulin 10u, shifting K into cells for 15 - 30 min, max 30-60 min.
  • Hemodialysis.
• Severe: > 6.5 mmol/L
  • IV fluids
  • Glucose 25g + Insulin 10u
  • Salbutamol 5 (20) mg inhaled, or Fenoterol IV, takes effect after 15 - 30 min.
  • Bicarbonates if metabolic acidosis.
  • Calcium Chloride(CaCl2) 10 ml 10% antagonizes K effect on cardiomyocyte membrane in 1-3 minutes.
  • Hemodialysis.

Other conditions

• Hypo-Kalemia- Severe < 2.5 mmol/l
  • Use CVC
  • 15% KCl – 20 mmol/h where 1ml= 2 mmol
  • Infuse in unstable patients when administered -20 mmol/10 min than 10 mmol/10 min
  • Mg supplementation
• Hiper-Calcemia
  • IV fluids
  • Furosemide 1 mg/kg iv
  • Hydrocortisone 200-300 mg iv
  • Pamidronate 30 – 90 mg iv
• Hyper-Magnesemia
  • IV fluids
  • CaCl2
  • Furosemide 1 mg/kg iv
  • Ventilatory support should be provided

Acute Coronary Syndrome

• Diagnosis relies on presentation, ECG findings, and Troponin levels.
• Further classification includes: Non-cardiac, UA, Other Cardiac, NSTEMI, STEMI
  • STEMI - ST-elevation myocardial Infarction.
  • NSTEMI = non-ST-elevation myocardial infarction.
  • UA = unstable angina.

AMI: In Hospital Treatment

• Revascularization via angioplasty/fibrynolysis/CABG.
• Heparin or biwalirudine/fondaparynux.
• Antiplatelet drugs (ASA+ thienopirydynes/ticagrelor,+/- inhibitors of GP IIb/IIIa)
• After Revascularization follow up with drugs like ASA+ thienopirydynes/ticagrelor, B-Blockers, ACEI/ARB, Statins, Nitrates, and antidysrrhythmics for selected patients.

AMI: Immediate Treatment

• M Morfine for pain and pulmonary edema
• O Oxygen if SaO2 < 95 %, dyspnea
• N Nitrates for pain, pulmonary edema, if BP>100mmHg
• A Aspirin saturation dose 150-300 mg p.o or 80 - 150 mg i.v.
• L Loop diuretic for pulmonary edema
• I I.v. access
• S if STEMI transport to a hemodynamic unit for /thrombolysis
• A - Antiplatelets eg. clopidogrel/prasugrel, depending on proposed therapy

Acute Heart Insufficiency

• First act to treat acute causes such as:
  • Acute coronary syndrome – PCI/thrombolysis/CABG.
  • Pulmonary thromboembolism-thromboliysis (systemic/local).
  • Cardiac tamponade/heart defect – surgery.
  • Dysrrythmia – antidysrytthimc drugs, heart ablation.
  • Hypovolemia - fluids.
• Determine hemodynamic disturbances to determine Acute Heart Insufficiency Therapy!
  • Type I (hot and dry) Righ CO: No pulmonary congestion, with a morality of 2,2%.
  • Type II (hot and wet (50%)): Isolated pulmonary congestion and Right CO with a mortality of 10%, use 1. oxygen, orthopnoe 2. MF 3.Diuretics 4. vasorelaxants (NTG)
  • Type III (cold and dry (hypovolemic shock)): Low CO no pulmonary congestion and Mortality 22%. use Fluids.
  • Type IV (cold and wet (cardiogenic shock)): Low CO, Pulmonary congestion and motrtality 55%, 1. If right BP – vasorelaxants 2. If low BP – vasoconstrictors and inotropic drugs.

Acute heart failure

• Symptomatic TH:
  • Inotropic drugs: Beta agonists (NA, DA, Dobutamine), PDEI 3 (Milrynone, Enoxymone) and Levosimendan
  • Diuretics (loop - Furosemide) / Aquaretics (Vaptans)
  • Natriuretic peptides – Neziritide (hr BNP)
  • Vasodilators (nitrates): NTG or Isosorbite dinitrate to stabilize, decrease hypoxemia, increase tissue perfusion, and reduce symptoms

Bradycardia

• If below 40 bpm, BP is below 90 mmHg, patient exhibits ventricular dysrhythmias or heart insuff:
  • Use IV atropine - 0.5 mg up to 3 mg for stabilization.
  • Administer adrenaline 2-10 ug/min.
  • transdermal electrostimulation or alternative drugs like salbutamol, theophyllin, glycopyrrolate or dopamine

Severe Hypertension

• Eliminate the cause: Drug use, MAO, ketamine, ergometrine, CA, phe etc
• Administer vasodilators like: Hydralazine (5mg every 15 min), GTN (50mg/50ml; 3 ml/h).
• Administer SNP and MgSO4 (2g) – 1g/h.
• Administer Beta blockers like:Esmolol 25-100mg – 50-200 ug/kg/min or Labetalol 5-10 mg.
• Alpha-blockers like:Phentolamine 1mg
• Urapidyl 10 – 20 mg (+ effect on 5HT rec.)

Preffered drugs for hypertension:

• Peracted brain stroke: Use any effective hypotensive drug
• Peracted MI: BB, ACEI, ARB
• AP: BB, Calcium antagonist
• Heart insuff. Diuretics, BB, ACEI, antagonist of mineralocorticoid receptor
• Aortic aneurysm: BB
• AF prevention: ARB, ACEI, BB or antagonist of mineralocorticoid receptor
• AF control of ventricular rythm: BB, DHP Calcium antagonist
• Kindney insuff./Proteinuria: ACEI, ARB
• Disease of peripherial arteries: ACEI, Calcium antagonist

Paroxysmal AF

• With fast ventricular rhythm and hemodynamic instability, cardioversion is needed.
• If stable, Cordarone (- iv 300 mg / 5% glucose, then half dose up to 1200 mg/d), Beta-blockers or Digitalis

Pulmonary edema

• For acute LV insufficiency:
  • Patient needs to be in an "Orthopnoë” position.
  • Deliver Oxygen.
  • Administer Furosemide – iv boluses/infusion or MF.
  • Nitrates – iv infusion (only if BP is increased or normal).
  • Dobutamine – iv infusion.

Seizures

• Caused by drugs, Hypoxia, Hypoglycaemia, Alcohol, Ions disturbance or other causes.
• Treat with O2 and normalize Glucose and Ions.
• Administer BDA: diazepam / clonazepam / clobazam, Phenytoine / Phosphenytoine or barbiturate coma: tiopental to aid general Anesthesia.

Intoxication: General Considerations

• Fast and decisive action is crucial.
• Provide life support.
• Treat seizures if they occur.
• Follow steps to stop poison influx.
• Inhibit absorption and aggravation of elimination while normalising body functions and providing antidotes

Respiratory

• In patients with cyanosis, provide oxygen (100% no longer than 6-8h if possible).
• Manage toxic lung edema with oxygen, and treat Chlorine(Cl2), fosgen, aspiration.
• Inhaled GCS (even 5 doses every 10 min) 02
• Upper body elevation, Intubation (PEEP), Furosemide 40 – 80 mg iv, Ab - beta-lactams, Diazepam 10 mg iv.

Circulation: Treat

• Perform Resuscitation (defibrillation, Adrenaline, Atropine, lidocaine)
• Treat Heart failure (Dopamine, Dobutamine)
• treat Dysrhythmia with Atropine, Orcyprenaline, Lidocaine or Cordarone
• Treat Shock by adding fluids, catecholamines, GCS, antihistamines

Intoxication: Provide specific treatments

• Maintain water/electrolyte balance with 8,4% NaHCO3 or Arginine or lysine Hydrochloride
• To inhibit toxin abs.:Use (carbo medicinalis), Provocation of vomiting (only conscious), Gastic lavage and/or laxatives

Carbo medicinalis

• dosage: 0,5-1 g/kg.
• It also interrupts hepato-jejunal circulation

Vomiting

• Throat irritation, 30 g NaCl in glass of water (hypernatremia/ brain oedema if do not use in children)
• Ipecacuane sirup: 10 - 15 – 30 (adult) ml + 300 ml of fluids, Apomorfine:0,1 mg/kg sc or im + 10 mg ephedrine (against BP fall)

Gastric Lavage

• Perform for fluid toxins up to 2 h and solid toxins up to 4 h, longer time in cases of toxins that inhibits gastric empting - Barbiturates.
• Pour in 20 – 60 1 warm NaCl in fractions of 150 - 300 ml + At 1 mg intravenously, then drain.
• On the end: 30 – 100 g activated charcoal "CM".

Some Antidote Examples

• In Intoxication with Universal, use antidote CM.
• In Intoxication with Br, J, HCN, use antidote Na Thiosulfate that will generate Tetrothiosulphite Na and Na iodine.
• In Intoxication with Detergents, washing powders, use antidote Silicones that will reduce foaming.

More Antidote Examples

Aggravation of Elimination: Forced Diuresis

• Fluids 12 l (glucose + NaCl+KCl) + furosemide.
  • Try to remain neutral or use Alkalic (acetazolamid/NaHCO3). This is needed for Barbiturates and NSA.

Aggravation of Elimination: Recirculation

• Disruption of hepato-jejunal recirculation with repeated administration of CM or cholestyramine.
  • Effective with TCA, Digitalis, Muchroom ingestion and Antivitamines.

Aggravation of Elimination:

• Hemodialysis, Peritoneal dialysis, Hemoperfusion, ultrafiltration, hemofiltration, hemodiafiltration, and Plazmaferesis are available if more action is needed.

Even newer techniques include:

• cascade filtration
• cryofiltration
• thermofiltration
• immunoglobulin adsorption
• HELP

Extracorporeal treatments:

• Hemodialysis
  • This as a wide spectrum effective with alcohols, Chinine, Paraaldehyde, Salycylic acid and Li Salts
• Hemoperfusion
  • Effective in with Chinidine, Digoxin, Dizopiramide, herbicides, INH , Lidocaine , MTX Phenytoine, Theophillin Phosphoric acid esters that are able to intoxicate lipophylich subst and substances with lower distributions

Be careful on intoxications

• Always check list for the appropriate treatment.
  • Opioids - ventilation!!! or use Naloxon
  • NSA - Alkalic diuresis and administer vit.K
  • B-blockers - At, Isoprenaline or Glucagone
  • Barbiturates - ventilation, always use alkalic diuresis.
  • BDA - flumazenil
  • Phenothiazines - use Neostigmine and antiarrythmic th.
  • TCA -
    • Neostigmine
    • antiarrythmic and antiepileptic th, BDA, decreasing of temp, and NaHCO3