Critical Care Medicine – Principles, Clinical Practice and Treatment

Checklist for ICU Rounds

Ventilator treatment

Patients who, due to lung disease or other lung injury, are unable to breathe satisfactorily can be treated with a ventilator that ventilates the lungs. The ventilator is also described as a respirator. Breathing then occurs invasively via a closed tubing system with regulated and controlled pressure and flow in the airways. Normally, spontaneous breathing occurs with the help of negative pressure in the airways, where air is drawn into the lungs by the respiratory muscles. In contrast, in ventilator-generated ventilation, air is blown into the lungs using positive pressure. The ventilator’s compressed air is generated mechanically by a compressor that is normally located on the back of the respiratory system. A system of precision valves then controls the gas pressure, gas flow, and breathing frequency to the patient, which is regulated by the user digitally or analogously in different breathing modes. Varying breathing methods are often described as “modes” or “breathing modes” in the ventilator. A more convenient term would be “breathing method in the ventilator” or simply “ventilator settings.” The ventilator delivers a preset tidal volume or minute volume over a preset inspiration time and at a preset breathing frequency.

The most common ventilator settings in the respirator’s breathing patterns are volume controlled ventilation (VCV, 20-1500 ml/breath) or pressure-controlled ventilation (PCV, 5-60 cm H₂O in inspiratory pressure). The different ventilator settings are described in detail below.

Examples of various ventilator settings include:

• Volume Controlled Pressure Control (VCPC)
• Pressure Control (PCV)
• Volume Control (VCV)
• Bi-vent/APRV
• ASV Adaptive Support Ventilation
• SIMV (PC) + PS
• SIMV (VCPC) + PS
• Automode PC + PS
• Automode VCPC – PS
• Pressure Support (PS)/CPAP (PS/CPAP)
• Volume Support (VS)
• Neurally Adjusted Ventilatory Assist (NAVA)

Ventilator treatment relieves the work of breathing but can unfortunately add further damage to already sick or injured lungs due to pressure injuries, atelectasis, pneumothorax, or infections.

To minimize the risk of injuries due to ventilator treatment, it is desirable to be able to tailor the treatment for each individual patient and stress the lung tissue as little as possible. Controlled ventilation involves significant changes in lung volume changes and airway pressures. Gas exchange in the lungs is affected by both ventilation and circulation. Common causes of respiratory failure include pulmonary edema, pneumonia, sepsis, atelectasis, severe COPD, or asthma. Other causes may be major trauma, lung contusions, head trauma, stroke, drug overdose, poisoning, unclear unconsciousness, or a severely ill and exhausted patient. Controlled ventilation is usually performed with a respirator. The patient is either intubated endotracheally (invasive ventilation) or ventilation occurs with the help of a tightly fitting mask, non-invasive ventilation (NIV). The tube or breathing mask is connected to the respirator’s tubing system and its breathing gases.

Ventilator treatment is usually volume-controlled (VCV) or pressure-controlled (PCV). Volume-controlled ventilation means that the volume given in each breath is predetermined, and pressure-controlled ventilation means that the pressure given in each breath is predetermined. Volume-controlled ventilation always provides a constant flow in the inhaled air, while in pressure-controlled ventilation, a decelerating flow is achieved. Pressure-controlled ventilation favors gas distribution and provides lower peak pressure compared to volume-controlled ventilation. Volume-controlled ventilation reduces the risk of hypoventilation and can be beneficial in ARDS. The time the patient is treated with a ventilator is always minimized.

Ventilator settings in different degrees of pulmonary injury

Respiratory Failure and Ventilator Treatment in Severe Respiratory Failure

The text below is based on patients with severe COVID-19 infection but can be considered applicable to most patients with severe respiratory failure.

Patients Treated Outside the ICU

• O₂ supply with target SpO₂ 92-96%; in patients with COPD or risk of CO₂ retention, target SpO₂ 88-92%.
• When O₂ supply, including delivery with a reservoir mask, is insufficient, high flow via nasal cannula (HFNC, “Optiflow”) is recommended.
• When HFNC is insufficient, CPAP with pressure ≤ 10 cm H₂O can be tried.
• Experience shows that COVID-19 patients who are entirely dependent on NIV, i.e., cannot maintain sufficient gas exchange without NIV, often continue to deteriorate. This can lead to the need for emergency intubation, which increases risks for the patient and the risk of infection spread. For patients with less pronounced lung failure, NIV may be an alternative used for longer periods, possibly alternating with HFNC. Similarly, NIV can be used for patients where intensive care is not considered but avoided if palliative care has been switched to.
• HFNC, CPAP, and NIV carry a risk of aerosol formation and infection spread, which strengthens the indication for protective equipment. Compared to CPAP/NIV, HFNC may offer an advantage through less need to be very close to the patient.
• HFNC and NIV should not be used during hospital transport; instead, use a reservoir mask.
• Mobilization, cough assistance, and position changes are essential to prevent and treat impaired lung function. It has proven particularly effective with prone or lateral position, with or without other respiratory support such as HFNC, NIV, or CPAP.

Potential Indications for Intensive Care

• PaO₂/FIO₂ < 20 kPa or worsening with increasing FIO₂ need (O₂%), SpO₂ <93% with O₂ ≥ 10 L/min on the mask.
• Rising PCO₂ (> 6.0 kPa), especially if pH < 7.30.
• Increased work of breathing and/or respiratory rate (RR) > 30/min. Ask the patient if breathing has improved or worsened over time.
• When NIV is used for patients because oxygen on a reservoir mask or HFNC is insufficient treatment and the patient continues to deteriorate or has not improved within 1-2 hours after starting treatment.
• Impaired consciousness level.
• Hypotension, oliguria, elevated and rising P-Lactate, heart echo with pronounced right and/or left failure.
• Before contacting the ICU, treatment limitations should usually have been discussed on the caring unit already before the patient is placed on a respirator. If the patient meets any ICU indication, contact the ICU simultaneously with this discussion. The responsibility for this lies primarily with the responsible doctor on the ward where the patient is being cared for.

Intubation

The intubation procedure is associated with an increased risk of circulatory/respiratory collapse and infection for staff, especially the person intubating. COVID-19 patients may appear relatively unaffected despite significant hypoxia and high respiratory rate. They can deteriorate very quickly and then find it very difficult to recover after intubation. Therefore, it is strongly recommended not to wait too long to intubate. Intubating COVID-19 patients always carries an increased risk of infection spread. For the procedure and checklist, see the specific guideline, link.

Recommendations Regarding Ventilator Treatment

Humidification/Filter

Secretion stagnation and “tube stop” are relatively common; active humidification with conventional equipment is preferred. If active humidification is not used, passive humidification with HME with filter function is given. Always use a filter at the ventilator’s expiratory inlet. All filter/hose changes are made with the ventilator in standby mode

. Auto-PEEP and patient-ventilator dyssynchrony may be due to filters that need to be replaced—especially if the patient has active humidification and/or inhalations. Testing of new hoses can be skipped in consultation with the responsible physician.

Closed Suction System

Always used in COVID-19.

Tidal Volume/Driving Pressure

Generally, tidal volume up to 8 ml/kg PBW is accepted if driving pressure ≤ 15 cm H₂O and plateau pressure ≤ 30 cm H₂O. Larger tidal volume/driving pressure is accepted when reduction is impossible or requires measures that are judged to worsen the situation, such as increased sedation, need for relaxation, or impaired gas exchange.

PEEP

Chosen individually, if good compliance, often 6-12 cm H₂O even with higher FIO₂. Try higher PEEP if lower compliance and low PaO₂/FIO₂. Reassess high PEEP by reduction with 2 cm H₂O and follow-up of tidal volume, compliance, and gas exchange. Note that compliance can only be assessed during controlled ventilation.

SpO₂/PaO₂– Target Values

• 88-94%, 7.5-9.5 kPa if controlled ventilation
• 92-94% 8.5-9.5 kPa if supported ventilation

PaCO₂

Up to 8.0 kPa is generally accepted. Higher PaCO₂ can be accepted if pH > 7.20 with a reasonable breathing drive. Higher PaCO₂ can also be accepted if ventilation otherwise involves excessively high tidal volumes/driving pressures or significant auto-PEEP.

Lung Recruitment

Consider early if low PaO₂/FIO₂ and low compliance, especially if sudden deterioration. Exclude bronchial intubation, secretion/threatened tube stop, pneumothorax. Do not repeat recruitment if the previous recruitment has had no effect.

Patient-Ventilator Dyssynchrony

Handled primarily by adjusting ventilator settings and increasing sedation, secondly with muscle relaxants intermittently or infusion, which should be re-evaluated after 12-24 hours.

Prone Positioning

Recommended if PaO₂/FIO₂ < 20 kPa and even with PCO₂ problems, aim for at least 16 h/day, daily turning with 4-6 h in the supine position.

Weaning

Due to slow improvement and the risk of “relapse,” regular weaning from the ventilator begins relatively late in the course of COVID-19 infection and first at lower ventilator settings than is otherwise common.

Humidification/Use of Filter in the Ventilator Circuit (Hoses) in Suspected or Confirmed COVID-19

Balance between risk of infection spread and what is optimal for the patient.

• Make a patient- and situation-based choice between active and passive humidification. Active humidification is preferred. The indication for active humidification is particularly present in pronounced hypercapnia with the need to eliminate dead space or in the presence of tough/dry secretion. Dry/tough secretion can cause tube stop or auto-PEEP. If active humidification is not possible, consider, e.g., acetylcysteine inhalations but via a “closed” nebulization system.
• Passive humidification is done primarily with HME (heat-moisture exchanger) which also has a filter function. This should be placed as close to the tube as possible, but the closed suction system must be between the tube and the HME/filter.
• If HME with filter function is lacking, use another HME supplemented with a filter at the ventilator’s inspiratory outlet.
• There should always be a filter at the ventilator’s expiratory inlet.
• If active humidification is used, HME/filter at the tube should not be used, but there should be a filter at the ventilator’s inspiratory outlet.
• During all filter changes, hose changes, and similar, the tube should be briefly clamped and the ventilator set to Stand-By before disconnecting. The ventilator should not be restarted until everything is reconnected. For tracheostomized patients, this is done the same way but without clamping.

Invasive Ventilation

• With pressure control, choose driving pressure for the desired tidal volume, then adjust RR to the desired minute ventilation and acceptable PaCO₂ but avoid auto-PEEP.
• Accept tidal volume around 8 ml/kg PBW (predicted body weight) if driving pressure ≤ 15 cm H₂O (driving pressure = pressure over PEEP, the ventilating pressure). Gradually aim for lower tidal volume/kg PBW if the driving pressure is higher.
• Note that driving pressure can only really be assessed during controlled ventilation. During pressure-supported ventilation, it is suggested to accept tidal volumes up to 8 ml/kg PBW provided that the support is max 14 cm H₂O and the patient does not “pull” much on inhalation. If this cannot be achieved, controlled ventilation or measures to reduce the breathing drive, e.g., increased sedation, are suggested.
• Note that the reduction of pressure support to reduce tidal volume often has little effect but leads to increased work of breathing. Therefore, it is rarely appropriate to have pressure support < 8-10 cm H₂O. In cases of high tidal volumes, it may be correct to increase pressure support if the patient has significant work of breathing. The result is often unchanged tidal volume but with reduced work of breathing. The alternative is to switch to controlled ventilation.
• Larger tidal volume/driving pressure is accepted when reduction is impossible or where the alternative is measures that are judged to worsen the situation, such as deeper sedation, need for muscle relaxation, impaired gas exchange, pronounced patient-ventilator dyssynchrony.
• The goal is peak pressure ≤ 30 cm H₂O and driving pressure ≤ 15 cm H₂O. Always strive for the lowest possible driving pressure.
• FiO₂ with target SpO₂ 88-94%, and 92-94% if pressure-supported ventilation.
• PEEP is chosen individually, often 6-12 cm H₂O. Often, lower PEEP is chosen than in other ARDS, especially if the patient has high compliance (> compliance 30 ml/cm H₂O).
• If high FIO₂ is needed, i.e., moderate-severe ARDS, higher PEEP can be tried, especially with low compliance. If higher PEEP does not improve gas exchange or compliance, or if increased PEEP leads to hemodynamic deterioration, revert to lower PEEP. Similarly, PEEP > 8-10 cm H₂O should be reconsidered at least daily, but first, ask for the effect of previous attempts at reduction. Changes are made in steps of 2 cm H₂O.
• Hypercapnia due to impaired CO₂ elimination is accentuated by high PEEP, especially in relative hypovolemia. Consider giving volume and reducing PEEP; lower PEEP may be better overall even if it requires increasing FIO₂.
• Consider early lung recruitment with increased PEEP and increased airway pressures if the patient has low PaO₂/FIO₂ and low compliance (< c. 20 ml/cm H₂O) but recruit with increased caution in hypovolemia/hemodynamic instability. Do not repeat recruitment attempts if previous ones have had no effect.
• Patient-Ventilator dyssynchrony. When the patient is difficult to ventilate and does not follow the ventilator (“breathes against it”), it is managed with increased sedation (including increased opiate dose). If this is not sufficient, repeated doses of muscle relaxation or infusion for up to 24-48 hours can be tried. In cases of severe gas exchange disorders, caution is advised when switching from supported to controlled ventilation. The risk is that this switch can cause respiratory collapse. The solution may be a quick return to spontaneous breathing with supported ventilation, e.g., with reversal of drugs.

Avoid aerosol formation by avoiding disconnection of ventilator hoses/tubes as much as possible. This recommendation also aims to avoid derecruitment (atelectasis formation).

• Use closed suction system.
• Avoid inhalation treatment except for strong indications.
• Minimize the number of bronchoscopies. Bronchoscopy is performed for diagnostics and when there is an imminent risk of tube stop. Use muscle relaxants during bronchoscopy, but be prepared for reversal (see comment in the section on patient-ventilator dyssynchrony above). Blind protected brush is an alternative for diagnostics.
• If disconnection is unavoidable, the ventilator should be set to Stand-By and the tube clamped with a clamp. Consider a sedation bolus before doing this. Switch to active ventilation only when all hoses are connected.

Prone positioning for at least 16 hours/day is recommended if PaO₂/FIO₂ < 20 kPa in the supine position. Prone positioning in COVID-19 ARDS often has a favorable effect and can therefore be tried at higher PaO₂/FIO₂, e.g., in gradual deterioration of oxygenation or when the problem is more hypercapnia than hypoxemia. If “true prone positioning” is difficult to achieve, the prone lateral position is an alternative. In both cases, small adjustments should be made so that pressure points and the position of the head/neck change regularly.

Other ventilation methods: There are no studies showing clear advantages of using other ventilation methods than pressure control and pressure support. In the current situation, with very varying experience and competence among both doctors and nursing staff, it is recommended to refrain from using ventilation methods not commonly used. In other words, only use pressure control and pressure support. Pressure-controlled ventilation with controlled tidal volumes, such as VCPC, is used in special cases where stable PaCO₂ levels are required.

Sedation/Weaning

If the patient has well-functioning controlled ventilation, do not rush to switch to pressure support. Wait until PaO₂/FIO₂ ≥ 33 kPa (corresponding to approximately SpO₂ 95% at FIO₂ 0.3) and the patient does not breathe with too large tidal volumes (e.g., > 10 ml/kg PBW) during supported ventilation. For the same reason, PEEP should not be reduced to <6 cm H₂O until a relatively late stage in the course. Markedly impaired oxygenation during turns indicates that the patient is not ready for extubation. Experience so far is that patients with COVID-19 ARDS require at least 10-14 days of intensive care. During ongoing intensive care, the patient should be considered contagious. Extubation should be done later in the course, i.e., in a situation where the need for continued respiratory support after extubation is judged to be low.

Extubation: Several centers have reported airway obstruction after extubation; it is unclear if and why this may be more common in COVID-19 than in other pneumonia/ARDS. Secretion stagnation problems are common after extubation, managed in the usual way with cough assistance and mobilization. Tracheotomy may, in selected cases, carry less risk of reintubation and allow for a quicker conclusion of intensive care, but it assumes that the patient can be transferred to care units with the right competence and staffing.

Refractory hypoxemia/hypercapnia: Possible measures include recruitment, prone positioning, optimizing PEEP (which may mean lowering PEEP), minimizing apparatus dead space, hemodynamic assessment/optimization (exclude hypovolemia as a cause of impaired CO₂ elimination), deepened sedation, neuromuscular blockade, treating fever, accepting spontaneous breathing/supported ventilation despite larger tidal volumes/airway pressures than desired, inhalation of vasodilating drugs (positive experiences have been reported from inhalation of iloprost and milrinone), consultation with ECMO. A high frequency of pulmonary embolism has been described in COVID-19 patients, strengthening the indication for diagnostics in this regard.

ECMO: Consider contacting ECMO if the patient does not improve with the above-mentioned measures and severe hypoxemia persists (e.g., PaO₂/FiO₂ <10 kPa) and no contraindications are present. The indication for ECMO may change during the epidemic.

Tracheotomy: Use protective equipment, use muscle relaxants to avoid coughing, preferably cover the face/tube with a plastic sheet, put the ventilator in standby when the tube is retracted, and the trachea is incised. Ensure all hoses are connected, and the cannula is cuffed before the ventilator is restarted. See the link for a description of ARDS in COVID-19 and references.

Ventilator treatment (Graphic Illustration)

Ventilator treatment of ARDS

Definition of ARDS

• Acute lung failure (≤ 7 days)
• Lung failure is not entirely explained by heart failure
• Bilateral infiltrates (x-ray/CT/ultrasound)
• PaO₂/FiO₂ < 40 kPa despite PEEP 5 cm H₂O

Grading of ARDS

General Recommendations

• Avoid positive fluid balance if possible, increasingly important with a higher degree of ARDS.
• With increasing degrees of ARDS, there is an increased need for hemodynamic evaluation (heart echo) and special measures if right heart failure is present.
• Ensure adequate diagnosis and treatment of the etiology, infection diagnostics, and infection treatment.
• The level of sedation is chosen for patient comfort, avoid excessive work of breathing (if PS), and avoid patient-ventilator dyssynchrony.
• Prophylaxis regarding DVT, stress ulcer, VAP, and pressure ulcers.

Decision support at early ARDS on ventilator treatment

ARDS in severe pulmonary infection

In ARDS, there is often, but not always, a correlation between the degree of oxygenation problems (lower PaO₂/FiO₂) and lower compliance. This is due to large lung areas that are not air-filled/ventilated. When a smaller portion of the lungs is ventilated, compliance is low, and blood flow through unventilated areas becomes an intrapulmonary shunt, which in turn explains hypoxemia that responds poorly to increased FiO₂. With this pathophysiology, improved oxygenation and compliance are often, but not always, seen with increased PEEP and after lung recruitment with high airway pressures. The mechanism is then that lung areas that were not previously air-filled/ventilated open up, which in turn means that larger portions of the lung are ventilated, leading to better compliance and less shunt. This is the logic when the need for increased FiO₂ is linked to the use of higher PEEP (PEEP-FiO₂ tables). In recent months, there has been intense discussion about whether COVID-19-induced ARDS systematically differs from ARDS caused by other pneumonias. In several, relatively large, patient materials, it has been challenging to demonstrate clinically significant differences in compliance.

At the same time, we have also locally experienced that it is relatively common to see a combination of severe ARDS (low PaO₂/FiO₂ ratio) and relatively high (almost normal) compliance, but this also occurs in ARDS of other etiologies than COVID-19. For all patients with ARDS, regardless of etiology, the choice of treatment, such as ventilator settings, needs to be continuously adapted to the current situation. An example of this is when severe oxygenation problems (low PaO₂/FiO₂) are associated with well-preserved, almost normal, compliance. Preserved compliance indicates that low PaO₂/FiO₂ is not explained by lung areas without ventilation, which in turn means that there are worse conditions for higher PEEP to improve gas exchange or compliance. Preserved compliance and the absence of larger lung areas that are not air-filled/ventilated are consistent with the most common radiological findings in COVID-19 pneumonia: ground-glass type infiltrates and the absence of larger consolidated lung areas.

The oxygenation problem in this situation has instead been suggested to be due to V/Q mismatch combined with inhibited hypoxic vasoconstriction. It is in this situation that slightly lower PEEP and slightly higher tidal volumes become reasonable. High PEEP can, through several mechanisms, worsen gas exchange, especially CO₂ elimination. This is not specific to COVID-19 patients, but it becomes particularly important since it seems more common that PEEP does not open unventilated lung areas. The deterioration in gas exchange with increased PEEP becomes more pronounced if the patient is also relatively hypovolemic. In preserved lung compliance, PEEP has a greater effect on preload than in ARDS with decreased compliance. Reduced cardiac output due to high PEEP and relative hypovolemia has been suggested to contribute to acute kidney failure in COVID-19 patients. Other patients with COVID-19 pneumonia describe a pathophysiology more typical of “usual” ARDS: decreased compliance and shunt due to lung areas that are not air-filled/ventilated combined with improved gas exchange with increased PEEP/lung recruitment. In this situation, the indication to limit tidal volume and try higher PEEP is strengthened.

The discussion about ARDS of different types will likely continue. Regardless, the collective experience suggests greater restraint with higher PEEP and acceptance of higher tidal volumes than in COVID-19 ARDS, but also that there may be patients/situations where the pathophysiology more resembles “usual” ARDS.

Coughing in the ventilator

Severe persistent cough can be a serious problem when treating intensive care patients in the ventilator and during weaning. Severe coughing is seen, among others, in:

• ARDS
• Recent tracheostomy
• COVID-19 infection
• Whooping cough (even past whooping cough)
• Sarcoidosis
• COPD
• Restrictive lung diseases – pulmonary fibrosis
• Tracheomalacia
• RSV pneumonia
• Lymphoma

Severe coughing in a patient on a ventilator can be treated with inhalation in a nebulizer (x 3-6) of:

• Lidocaine (Xylocaine) 10 mg/ml, 1 ml +
• Bupivacaine 5 mg/ml, 1 ml +
• NaCl 1 ml (total 3 ml), in nebulizer

This treatment can provide good cough suppression for a couple of hours. It can be given 3 to 6 times daily. An injection of lidocaine (Xylocaine) 50 mg intravenously before mobilization can also be tried with good results. Opiates given intravenously also provide some cough suppression. In cases of bronchospasm and coughing, an “asthma drip” can also be tried, administered over 12 hours:

• Glucose 5% 1000 ml +
• Theophyllamine (23 mg/ml) 20 ml +
• Betamethasone (Betapred) 8 mg

Asthma Drip

In cases of refractory bronchial obstruction or severe persistent coughing, a classic asthma drip can be given intravenously over 12 hours. This should not be given in a central venous catheter but peripherally.

• Glucose 5% 1000 ml +
• Theophyllamine (23 mg/ml) 20 ml +
• Betamethasone (Betapred) 8 mg (4 mg/ml)
• Possibly terbutaline (Bricanyl) 0.5 mg/ml 1 ml iv

Terbutaline (Bricanyl) can also be given subcutaneously, usually 0.25 mg = 0.5 ml x1.

Circulatory Failure and Blood Pressure Elevating Treatment

Inotropic treatment refers to intravenous vasopressor treatment with potent short-acting vasoactive drugs. The drugs commonly used are synthetic fast-acting catecholamines. These drugs are administered intravenously either intermittently or as a continuous infusion via a central venous catheter (CVC) or a peripheral venous catheter (PVC). The treatment usually, but not always, results in increased blood pressure, increased cardiac output, and increased oxygen transport. The catecholamines activate α and β receptors in vital organs and peripheral vessels. Αlfa₁-receptors are primarily found in peripheral blood vessels postsynaptically, β₁-receptors are mainly in the heart, β₂-receptors are in the heart, blood vessels, uterus, and airways. DA₁-receptors are primarily found in the splanchnic and kidneys. Vasopressor substances have short-lived sympathomimetic effects on circulation with positive effects on blood pressure and oxygen delivery, but long-term use may pose risks for damage to vessels, extremities, and vital organs such as the heart and kidneys. There is an increased risk of heart arrhythmias and ischemia, but the risk depends on how the drugs are used. Common vasopressor substances include dopamine, adrenaline, noradrenaline, and dobutamine. Prolonged use may pose a risk of a fatigued heart leading to heart failure, as well as an increased risk of bowel ischemia and peripheral ischemia. In cases of moderate blood pressure drops, short-acting drugs like ephedrine and phenylephrine should be used as first-line therapy, but if longer-lasting effects are needed, continuous infusion of more potent drugs is recommended.

Suggested treatment for hypotension not responding to initial fluid therapy; In cases of low pulse < 90 beats/min and low blood pressure: First-line therapy is ephedrine 5-10 mg i.v., second-line therapy is dopamine, 2-10 μg/kg/min dosed according to pulse and blood pressure response, third-line therapy is adrenaline 0.1-1.0 mg i.v., followed by continuous infusion, 0.05-0.1-0.30 μg/kg/min dosed according to pulse and blood pressure response. In cases of high pulse > 90 beats/min and low blood pressure: First-line therapy alongside fluid therapy is phenylephrine 0.1-0.2 mg i.v., second-line therapy is dobutamine, 2-10-15 μg/kg/min or noradrenaline dosed according to pulse, blood pressure, CO, and SvO₂. Noradrenaline is administered as a continuous infusion, 0.01-0.1-(0.5) μg/kg/min = 3-40 ml/h for 70 kg. The usual starting dose of noradrenaline is 0.05 μg/kg/min, dosed according to blood pressure. Noradrenaline can also be used as a first-line agent in severely ill patients but should preferably not be given through a peripheral venous catheter due to the risk of hemodynamic instability.

Physiological Effects of Inotropic Drugs

Low Blood Pressure and Inotropic Drugs

Heart Failure – Perioperative Management

Chronic Heart Failure

• Prevalence ≈ 2%
• > 75 years, prevalence ≈ 8 %
• Within 10-20 years, the prevalence has increased 2-3 times
• Increased age
• Today, more people survive acute infarction but develop heart failure

Chronic Heart Failure – Clinical Syndrome

• Reduced ventricular function
• Increased pressure in the pulmonary circulation
• Reduced physical capacity
• Neuroendocrine activation
• Reduced survival

Pathophysiology of Heart Failure

• (MAP – CVP) = Cardiac output  x  SVR
• Cardiac output = SV x HRSV ↓ CO ↓

Pharmacological Treatment

• ACE inhibitors
• Angiotensin II receptor blockers
• β-blockers (metoprolol, bisoprolol, carvedilol)
• Aldosterone receptor antagonists
• Digoxin

ACE inhibitors, angiotensin II rec. blockers

• Reduces angiotensin II
• Reduced catecholamines
• Reduced aldosterone
• Reduced ADH
• Increases bradykinin
• Increases NO
• Increases MPGI₂
• Reduced production of tissue angiotensin II
• Antiproliferative effect
• Reduces remodeling

β-blockers (metoprolol, bisoprolol, carvedilol)

• Reduces MVO₂
• Increased glucose uptake
• Improved energy utilization
• Antiarrhythmic effect
• Reduced Ca²⁺ leakage from SR
• Antiapoptotic effect
• Antioxidant

Aldosterone receptor antagonists

• Reduced myocardial collagen
• Lowers catecholamines
• Improves baroreflex
• Improves endothelial function (NO)

Brain Natriuretic Peptide (B-type natriuretic peptide, BNP)

• Produced in the left ventricle and released upon ventricular wall distension (increased preload)
• Released together with NT-proBNP, which is biologically inactive
• Vaso-venodilation, increases GFR, natriuresis, inhibits RAAS
• Longer half-life than ANP

Prognostic Value of Natriuretic Peptides (BNP, NT-proBNP)

• Preoperative elevation of BNP/NT-proBNP increases the risk for:
  • MACE (OR: 19.8)
  • Mortality (OR: 9.3)
  • Cardiac death (OR: 23.9)
• “Cut-off” level?
• Method
• BNP/NT-proBNP in relation to other methods?

NT-proBNP Reference Values

• < 400 ng/l heart failure unlikely
• 400-900 ng/l possible heart failure
• > 900 heart failure likely

Perioperative Management

• Identification of high-risk patient (EF, NT-proBNP, clinic)
• Is the patient optimally treated for heart failure?
• What do we do with “heart failure medication” before surgery?

Pharmacological Treatment

• ACE inhibitors, angiotensin II receptor blockers
• β-blockers (metoprolol, bisoprolol, carvedilol)
• Aldosterone receptor antagonists
• Diuretics
• Digoxin

Perioperative Management

• Identification of high-risk patient (EF, BNP, clinic)
• Is the patient optimally treated for heart failure?
• What do we do with “heart failure medication” before surgery?
• Choice of anesthesia technique (regional, general anesthesia?)

Surgery in Lower Body

Regional anesthesia in primary heart failure and heart failure secondary to:

1. Aortic insufficiency
2. Mitral insufficiency

Case Report

• 37-year-old woman with twin pregnancy at week 33. Seeks emergency care due to shortness of breath and leg swelling. Previously heart-healthy.
• BP: 110/60, HR: 120, SpO2 90%
• Slight elevation of CK-MB. ECG: repolarization disturbance.
• Echo shows biventricular failure. LVEF: 20% MI, TI grade 3/4.
• Treatment started with furosemide and nitroglycerin infusion

Decision for emergency C-section. Anesthesia technique?

Anesthesia Induction in Heart Failure

• Hypnotics:
  • thiopental
  • midazolam
  • ketamine
  • propofol
• Opioids (fentanyl)

Hemodynamic effects of Anesthetics

Anesthesia Induction with Propofol (2 mg/kg + 0.1mg/kg/min) and its Effects on Muscle Sympathetic Activity (MSA), MAP, and HR

Maintenance of Anesthesia

• TIVA (propofol, opioid)
• Inhalation anesthesia

Intraoperative Monitoring in Heart Failure

• Invasive blood pressure
• 2-3 lead ECG, ST trend
• CVC
• PA catheter?
• TEE – in case of severe hemodynamic instability

Inotropic Drugs

• Adrenaline
• Noradrenaline
• Isoprenaline
• Dopamine
• Dobutamine
• Phosphodiesterase inhibitors
  • amrinone
  • milrinone
  • enoximone
• Calcium sensitizers
  • levosimendan

Inotropic Drugs

• Noradrenaline (Norepinephrine)
• Adrenaline (Epinephrine)
• Dopamine
• Dobutamine
• Isoprenaline
• Levosimendan
• Milrinone

Recommendations

• Identify high-risk patient
• Arterial line, CVC (the day before)
• Monitor arterial pressure (MAP), central venous saturation before induction
• Connect milrinone and noradrenaline (NA) to CVC
• Use anesthesia technique you are familiar with
• Maintain MAP (65-75 mmHg) with NA
• Maintain central venous saturation (≈ 60-70%) with milrinone
• Administer fluids based on CVP
• Hemoglobin > 100 g/l
• Have two anesthesiologists at the start of anesthesia!

Diastolic Heart Failure

• Myocardial relaxation
  • Active, energy-requiring process
  • Affected by ischemia and
  • Inotropic drugs
• Passive filling
  • Extracardiac factors
  • Structural factors

Diastolic Dysfunction

Definition:

• Normal filling pressure results in inadequate filling of the LV
• Elevated filling pressure is required for adequate LV filling
• 40-50% of heart failure patients have isolated diastolic dysfunction

Isolated Diastolic Dysfunction

• Hemodynamics similar to systolic failure
• LVEF is normal, LVEDV low
• LV hypertrophy
• Abnormal mitral Doppler (E/A <1)
• Hypertension, aortic stenosis
• Dynamic LV outflow obstruction (functional aortic stenosis)

Treatment of LV Outflow Obstruction with SAM

• Increase preload (“volume challenge”)
• Avoid tachycardia
• No inotropic agents
• No vasodilators
• In case of tachycardia, administer β-blockers
• Guide therapy with echo-Doppler!!!

Pulmonary Hypertension and Right Ventricular Failure

The Pulmonary Circulation and Right Ventricle

Interaction between RV and LV (“ventricular interdependence”)

• Changes in pressure/volume in one ventricle directly affect the pressure/volume in the other ventricle
• Immediate force transmission between RV and LV
• Shared muscle fibers, septum, pericardium
• Diastolic and systolic interaction

Diastolic Ventricular Interaction with RV Pressure/Volume Loading

• Increased volume/distension of RV during diastole, septum shifts to the left
• Reduces LV volume, i.e., reduced LV preload
• LV end-diastolic pressure (PCWP) increases
• LV compliance decreases

Systolic Ventricular Interaction with RV Pressure/Volume Loading

• With RV pressure/volume loading, a flattened septum shifts from left to right during systole
• LV assist is more effective at high systemic pressure
• RV function deteriorates at low systemic pressure (peripheral vasodilation)

Pulmonary Hypertension

• MPAP > 25 mmHg or SPAP > 55 mmHg
• Right ventricular hypertrophy/failure
• Classification:
  • Pulmonary arterial hypertension
    • Primary, idiopathic pulmonary hypertension (sporadic, familial)
    • Related to collagen vascular diseases (scleroderma, lupus, RA)
    • Portopulmonary hypertension
  • Pulmonary venous hypertension (LV failure, MI/MS, AS)
  • Pulmonary hypertension associated with lung disease
  • Pulmonary hypertension caused by thromboembolism

Anesthetic Considerations in Pulmonary Hypertension

Anesthesia in Primary/Secondary Pulmonary Hypertension and RV Failure

• Maintain chronic medication for pulmonary hypertension (Ca²⁺ antagonists, sildenafil, ET antagonists, i.v. PGI₂)
• Intravenous PGI₂ is switched to inhalation
• Mild premedication
• Insertion of PA catheter before induction (CVP, PA)

Anesthesia in Primary/Secondary Pulmonary Hypertension and RV Failure

• TIVA (propofol/opioid).
• Avoid ketamine, N₂O (increases PVR) and inhalation agents (negative inotropic effect)
• TEE for monitoring RV function
• Hypoxia and hypercapnia increase PVR
• Regional anesthesia: undesirable drop in blood pressure and RV failure
• Noradrenaline for high SVR (MAP)
• Inhalation NO, prostacyclin and/or milrinone (selective reduction of PVR)
• In case of RV failure, i.v. milrinone + noradrenaline

Conclusions

• The prevalence of chronic heart failure is continuously increasing
• Understand the pathophysiology
• Identify high-risk patient
• Anesthesia technique is less important
• Adequate monitoring
• Use inotropic/vasoactive drugs
• Do not forget the diagnosis of dynamic LV outflow obstruction in cases of sudden and severe intraoperative cardiogenic shock
• Noradrenaline + inhalation of vasodilators in pulmonary hypertension and RV failure

Treatment of Heart Failure with Inotropic and Vasoactive Drugs

Chronic Heart Failure

• Prevalence ≈ 2%
• > 75 years, prevalence ≈ 10 %
• Within 10-20 years, the prevalence has increased 2-3 times
• Increased age
• Today, more people survive acute coronary syndromes

Inotropic Treatment

• Acute decompensation of chronic heart failure (ICM, DCM)
  • hypotension
  • hypoperfusion
• Acute coronary syndrome
  • extensive myocardial damage LV, RV
  • VSD, papillary muscle rupture (MI)
• “Myocardial stunning” after revascularization
• Postoperative failure after cardiac surgery/transplantation
• Septic shock – septic cardiomyopathy
• Myocarditis
• Postpartum cardiomyopathy
• Right ventricular failure (pulmonary embolism, ARDS)

Inotropic Drugs

• Adrenaline
• Noradrenaline
• Isoprenaline
• Dopamine
• Dobutamine
• Phosphodiesterase inhibitors
•         milrinone
• Calcium sensitizers
•         levosimendan

Adrenaline (Epinephrine)

• Dosage in ng/kg/min
  •       10-30 ng/kg/min: beta 1, 2 stimulation
  •       30-100 ng/kg/min: alpha + beta stimulation
  •       > 100  ng/kg/min: alpha stimulation
• Tachycardia
• Vasoconstriction
• Arrhythmias

Noradrenaline (Norepinephrine)

• The beta receptor stimulating effect corresponds to that of adrenaline
• Stimulates alpha receptors at low concentrations
• Given at low SVR and hypotension
• Sepsis and “Systemic inflammatory response syndrome” (SIRS)
• Less tachycardia and arrhythmias compared to adrenaline
• Dosage: 0.01-0.1-(0.5) μg/kg/min = 3-40 ml/h for 70 kg. Usual starting dose 0.05 μg/kg/min, adjusted according to blood pressure.

Isoprenaline

• Beta-1, 2 stimulation only
• Positive inotropic and chronotropic effect
• Vasodilation and hypotension
• Given in bradyarrhythmias and AV block
• Dosage: 0.01-0.15 μg/kg/min, 15-30 ml/h for 70 kg. Usual starting dose 0.05 μg/kg/min, adjusted according to blood pressure.

Dopamine

• Dosage in µg/kg/min
  • 0.5-2.5 µg/kg/min: stimulates dopamine receptors
  • 1-10 µg/kg/min: beta receptor stimulation
  • 5-10 µg/kg/min: alpha stimulation
• Tachycardia, arrhythmias
• Lowers SVR at low doses
• Vasoconstriction, SVR, and PCWP increase with increasing doses
• Increased MVO₂
• Good in heart failure and hypotension

Dobutamine

• Beta-1, 2 stimulation (d-dobutamine), SVR unchanged
• Alpha stimulation (l-dobutamine), SVR unchanged
• At higher doses, beta-2 effect dominates over alpha, MVO₂ unchanged/increase  i.e., SVR and PCWP decrease
• Tachycardia, arrhythmias MVO₂ unchanged/increase
• Dosage: 2-15 µg/kg/min

Limiting Factors in the Use of Catecholamines

• Downregulation of beta and alpha receptors
• Tolerance development
• Tachycardia, arrhythmias
• Does not improve survival in LV failure

Phosphodiesterase Inhibitors (milrinone)

• Less significant increase in heart rate compared to dobutamine
• Better vaso-venodilation compared to dobutamine
• Additive effect to β stimulants
• Does not increase MVO2
• Less pronounced tachyphylaxis compared to β stimulants

Levosimendan

Levosimendan – Hemodynamics

Calcium Sensitizers and Diastole

Levosimendan and Diastolic Function in the Clinic

• Patients (n=23) with AVR due to aortic stenosis
• Randomized postoperatively to:
  • placebo (n=11)
  • levosimendan (0.1 and 0.2 µg/kg/min) (n=12)
• Left ventricular isovolumetric relaxation time (IVRT)
• Heart rate, filling pressure, arterial pressure were kept constant with pacing, colloid, and phenylephrine

Inotropic and Lusitropic Effects of Levosimendan vs. Milrinone

• Patients (n=31) with AVR due to aortic stenosis
• Randomized postoperatively to:
  • milrinone 0.4 and 0.8 µg/kg/min (n=16)
  • levosimendan 0.1 and 0.2 µg/kg/min (n=15)
• Strain echocardiography (TEE):
  • LV strain (2-chamber, posterior wall)
  • RV strain (4-chamber, free wall)
  • Strain rate systole (SR-S)
  • Strain rate early diastole (SR-E)
• Heart rate, filling pressure, arterial pressure were kept constant with pacing, colloid, and phenylephrine

Inotropic and Vasoactive Drugs in Cardiogenic Shock

“At present, there are no robust and convincing data to support a specific inotropic therapy as the best solution to reduce mortality in hemodynamically unstable patients with cardiogenic shock complicating AMI.” Cochrane Database Syst Rev. 2014 Jan 2;1:CD009669. doi: 10.1002/14651858.CD009669.pub

Dopamine or Noradrenaline as Vasopressor in Cardiogenic Shock?

Adrenaline or Noradrenaline?

• 57 patients with AMI + PCI and cardiogenic shock
• Randomized to
  • adrenaline (n=27)
  • noradrenaline (n=30)
• Target MAP 65-70 mmHg
• Primary end-point: change in cardiac output over 72 hours
• Safety end-point: refractory cardiogenic shock

Levosimendan vs Dobutamine in Cardiogenic Shock

• 22 patients with STEMI and PCI
• Cardiogenic shock
• Randomized to:
  • levosimendan (n=11) 24 µg/kg + 0.1 µg/kg/min
  • dobutamine (n=11) 5 µg/kg/min
• No IABP

Levosimendan vs Enoximone (Phosphodiesterase Inhibitor) in Cardiogenic Shock

• Cardiogenic shock after PCI due to AMI
• IABP
  • noradrenaline (≈0.25 µg/kg/min)
  • dobutamine (≈10 µg/kg/min)
• Randomized to:
  • levosimendan (n=16)
  • enoximone (n=16)
• End-point: 30-day mortality

Inotropic and Vasoactive Drugs in Right Ventricular Failure

Right Ventricular Failure (RVF)

Cardiac Causes

• Coronary artery disease (RV infarction)
• Valvular heart diseases
• Cardiomyopathy (ischemic, dilated)
• Cardiac surgery (CABG, AVR, MVR)
• Heart transplantation
• Post-LVAD

Extracardiac Causes

• Pulmonary embolism
• Lung diseases (COPD, ARDS)
• Primary pulmonary hypertension
• Sepsis
• Lung transplantation
• Post-thromboendarterectomy
• 
• 
• 

Inhaled NO in RVF after posterior AMI

• Thirteen patients with RV infarction and cardiogenic shock
• Inhalation of NO (80 ppm)



Inhaled NO in heart transplantation and RVF



Inhalation of prostaglandins and milrinone – doses

• Prostacyclin  (Flolan^®): 10 µg/ml, 5-10 ml/h
• Iloprost (Ilomedin^®, Ventavis^®): 10 µg/ml, 2.5-5 µg x 6-9
• Treprostinil (Remodulin^®): 30-50 µg x 4
• Milrinone: 1 mg/ml, 5-10 ml/h
• 
• 
• 

Renal effects of inodilators

Increased cardiac output leads to an increase in RBF, affecting GFR?

• 
• 
• 
• 

Renal effects of milrinone

• Patients undergoing cardiac surgery with normal preoperative renal function (n=27)
• Two groups:
  • severe heart failure after weaning from CPB requiring milrinone  (n=8)
  • no heart failure after CPB (n=19)
• Systemic hemodynamics (PAC)
• Renal blood flow (RBF), renal vascular resistance (RVR), glomerular filtration rate (GFR), renal oxygen extraction (RO₂Ex)
• Measurements: T0 =30’after CPB, T1=60’ after CPB
• 
• 

Renal effects of levosimendan?

”Effects of Levosimendan on Glomerular Filtration Rate, Renal Blood Flow, and Renal Oxygenation After Cardiac Surgery With Cardiopulmonary Bypass: A Randomized Placebo-Controlled Study”

Bragadottir et al Crit Care Med 2013;41:2328

• Uncomplicated cardiac surgery, normal renal function
• ICU, sedated, mechanically ventilated
• Randomized to:
  • placebo, n=15
  • levosimendan, n=15, 12µg/kg + 0.1 µg/kg/min
• Systemic hemodynamics (PAC)
• Renal blood flow (RBF), renal vascular resistance (RVR), glomerular filtration rate (GFR) renal oxygen consumption (RVO₂), renal oxygen extraction (RO₂Ex), filtration fraction
• 
• 
• 

“Differential effects of levosimendan and dobutamine on glomerular filtration rate in patients with heart failure and renal impairment: a randomized double-blind controlled trial”

Lannemyr et al J Am Heart Assoc 2018;e008455

• Chronic heart failure (NYHA III-IV), LVEF < 40%
• Renal impairment: GFR < 80 ml/min
• Randomized to:
  • dobutamine 7.5 µg/kg/min (n=16)
  • levosimendan 12 µg/kg +0.1 µg/kg/min (n=16)
• Central hemodynamics
• Renal blood flow (RBF), GFR, renal oxygenation
• Renal vein catheter, infusions clearance of PAH and 51Cr-EDTA
• 
• 
• 
• 
• 

Conclusions

• Inotropic treatment is indicated for heart failure associated with hypotension/hypoperfusion
• Milrinone and levosimendan have similar hemodynamic effects
• Milrinone and levosimendan are equipotent in terms of inotropic and lusitropic effects on both LV and RV
• Norepinephrine is preferred over dopamine in cardiogenic shock
• Levosimendan is the only inotropic agent that increases GFR

Hypertension (refractory)

---

In cases of severe hypertension, patients may require intensive care. Difficult-to-treat severe hypertension is also known as refractory hypertension. Treatment usually begins with intravenous medication and then transitions to oral medication to achieve good blood pressure control. Uncontrolled high blood pressure puts significant strain on the heart and blood vessels and increases the risk of heart attack and ruptured blood vessels, such as in aortic dissection or subarachnoid hemorrhage. With intravenous treatment, the patient’s blood pressure is typically monitored using an arterial needle with continuous measurement of invasive blood pressure. Severe hypertension is usually defined as a systolic blood pressure over 180 mm Hg despite basic medication. Patients who may be candidates for intravenous blood pressure treatment include those with stroke, intracerebral hemorrhage (ICH), aortic dissection, other vascular dissection, pregnancy-related hypertension (preeclampsia), central stimulant intoxication (amphetamine), patients with pheochromocytoma, malignant hypertension, or renal artery stenosis. Blood pressure targets for these patients are usually established in consultation with another specialist, such as an internist, vascular surgeon, cardiologist, or endocrinologist.

The target blood pressure is often 120-140 mm Hg systolic, but this varies and is individualized depending on the underlying disease, kidney function, diuresis, and cerebral perfusion. The goal is to avoid risks of dissection, acute coronary syndrome, bleeding, and hypoperfusion of critical organs. Refractory hypertension is sometimes referred to as malignant hypertension.

Parenteral treatment of high blood pressure (intravenous treatment)

• Labetalol (Trandate) 1 mg/ml.  Administered as a bolus and/or continuous infusion. The infusion rate is typically around 160 mg/h but can be adjusted based on the response. The effective dose is usually 50 to 200 mg, but the infusion should continue until a satisfactory response is achieved, and higher doses may be required, especially in patients with pheochromocytoma.
• Dihydralazine (Nepresol). Vasodilator. 12.5 mg/ml. Administer 0.5 ml (=6.25 mg) IV in repeated small doses. Provides good blood pressure-lowering effect.
• Magnesium Sulphate (Magnesium). 0,5 mmol/ml. Administer 20 mmol magnesium sulfate as a bolus, followed by 20 mmol over 12 hours. Provides moderate blood pressure reduction.
• Metoprolol (Seloken) 1 mg/ml. Administered as a bolus and/or continuous infusion. Dose in continuous intravenous infusion 1-4 mg/h, adjusted according to pulse and blood pressure, 1-4 ml/h. Can be given in bolus doses of 1-2 mg at a rate of 1-2 mg/min.
• Nitroglycerin, 1 mg/ml. Dosage: Continuous infusion 1-5 ml/h, 20-80 μg/min, 0.2-1.6 μg/kg/min (max 10 μg/kg/min). Initial dose 0.5 μg/kg/min.
• Sodium Nitroprusside (Nipride) (0.5 mg/ml). Dosage: Continuous infusion 1-5 ml/h, 20-80 μg/min, 0.1-1.6 μg/kg/min. Initial dose 0.5 μg/kg/min increase by 0.5-1.0 μg/kg/min every 4-5 minutes until the desired effect is achieved or the systolic blood pressure has dropped to a minimum of 90-95 mm Hg systolic, ensure that urine production is not negatively affected.
• Clonidine (Catapres). Dosage: Continuous infusion 15 µg/ml 2-5 ml/hour, 0.25-1 µg/kg/h. Normal dose 0.33 µg/kg/h. Maximum dose in continuous infusion is 2 µg/kg/h.

Once invasive blood pressure control is achieved, the patient is often switched to broad oral therapy.

Oral blood pressure treatment

Typically, a triad of medications is used, such as a beta-blocker, an ACE inhibitor, and a calcium channel blocker. An example of effective oral blood pressure treatment might be:

• T. Metoprolol (Seloken) 50 mg x 4
• T. Enalapril 25 mg x 2
• T. Amlodipine 10 mg x 1

If this does not provide satisfactory blood pressure control, the following oral treatment options can be considered:

• T. Alfadil 4 mg x 2. Vasodilator.
• T. Clonidine (Catapres) 75 micrograms 2 x 3-6
• T. Physiotens (moxonidine) 0.4 mg x 2.
• T. Hydralazine 25 mg x 2. Vasodilator.
• T. Loniten (Minoxidil) 5 mg x 1-2. Licensed drug, vasodilator. Titrated up every third day.

The dosage is adjusted according to the underlying disease, kidney and liver function, pulse, and blood pressure.

Sepsis

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Background

Sepsis occurs when an infection affects the entire body, causing vital organs such as the heart, lungs, brain, and kidneys to stop functioning properly. Even a mild infection can sometimes develop into a severe or life-threatening condition. Those affected often feel very ill and have difficulty managing on their own. Symptoms of sepsis often appear suddenly, sometimes within a few hours.

Common symptoms of sepsis:

• Fever
• Chills
• Dyspnea, tachypnea, difficulty breathing
• Confusion
• Diarrhea or vomiting
• Severe abdominal pain, or pain in the back, muscles, or joints
• Muscle weakness (especially in the elderly)

You may not have all symptoms, but the more symptoms you have, the greater the likelihood of sepsis. Fever is common, but not everyone gets it.



Definition of sepsis

Sepsis is defined as an infection that causes a systemic response in the form of:

• Fever/hypothermia >38 ̊C or <36 ̊C
• Tachycardia >90 beats per minute
• Elevated respiratory rate >20 breaths per minute
• Leukocytes >12 x 10⁹/L or <4 x 10⁹/L

Early identification and appropriate treatment of patients with severe sepsis (blood poisoning) reduce mortality. Severe sepsis can affect anyone, but infants and the elderly are at increased risk, as are people with chronic diseases or weakened immune systems. Accurate prevalence data is lacking in Sweden, but it is estimated that 100–300 people per 100,000 inhabitants are affected each year. Mortality has previously been reported to be very high, with severe sepsis at 20% and septic shock at 45%. More recent studies suggest a mortality rate of around 15– 20%. Severe sepsis is one of the conditions with the highest mortality rates in an emergency department. According to international and national recommendations, patients with severe sepsis should receive appropriate antibiotic treatment within one hour of arrival at the hospital. Research has shown that early treatment with antibiotics, intravenous fluids, oxygen, and supportive care is crucial in severe sepsis. Inadequate initial antibiotic therapy in severe sepsis with positive blood cultures doubles mortality. Delayed adequate antibiotic treatment in septic shock increases mortality by almost 8 percentage points per hour during the first 6 hours. The more organ systems that fail and the higher the initial lactate level, the higher the mortality. This care program describes a sepsis chain for the acute management of patients who have or are suspected of having severe sepsis and septic shock. The goal of the sepsis chain is to early identify patients with an infection at risk of developing severe sepsis. As part of the sepsis chain, we have developed guidelines for pre-hospital, emergency department, and appropriate care unit management. The care chain is supported by cooperation between several parts of the healthcare system, with a focus on early identification and treatment without delay.



Sequential Organ Failure Assessment SOFA Score

Organ System	Score
	0	1	2	3	4
Respiration
paO2/FiO2, kPa	≥ 53,3	< 53,3	< 40	< 26,7 a	< 13,3 a
Coagulation
Platelets, × 109/l	≥150	<150	<100	<50	<20
Liver
Bilirubin, μmol/l	<20	20–32	33–101	102–204	>204
Circulation
Blood Pressure/Catecholamines	Mean arterial pressure ≥70 mm Hg	Mean arterial pressure <70 mm Hg	Dopamine <5 b or dobutamine (regardless of dose)	Dopamine 5,1–15 b or epinephrine ≤0,1 b or norepinephrine ≤0,1	Dopamine >15 b or epinephrine>0,1 b or noradrenalin >0,1 b
CNS
Glasgow Coma Scale or	15	13–14	10–12	6–9	<6
Reaction Level Scale	1	2	3	4–5	6–8
Renal Function
Creatinine, μmol/l and/or diuresis, ml/day	<110	110–170	171–299	300–440 <500	>440 <200
The original publication for SOFA also requires breathing support for 3 or 4 points [17]. The Swedish Intensive Care Register has chosen to abstain from this requirement, which we propose should apply as general Swedish practice.
FiO2 = fraction inspired oxygen; paO2 = partial pressure oxygen in arterial blood.
bUnits: μg/kg/min. Catecholamines should have been given for at least 1 hour.

New definitions diagnostic criteria and codes for sepsis and septic shock according to Sepsis

	Sepsis	Septic Chock
Definition	Life-threatening organ dysfunction caused by systemic response to infection	A subset of sepsis where underlying circulatory and cellular / metabolic disorders are sufficiently pronounced to significantly increase mortality
Diagnostic Criteria	Acute change infection corresponding to at least 2 SOFA points 1	Remaining hypotension requiring vasopressor to maintain mean arterial pressure ≥65 mm Hg with lactate> 2 mmol / l despite adequate fluid supply
Coding (ICD-10 SE)	R65.1 Sepsis, Sepsis-3 organ failure (increase of at least 2 SOFA scores) Systemic Inflammatory Response Syndrome [SIRS] of Infectious Source with Organ Weight 2	R57.2 Septic chock
1  If the 2-point increase is achieved by increment of 1 point in two organ systems, these changes should have taken place with sufficient simultaneousity: within 36 hours. SOFA = Sequential organ failure assessment.
2  Unfortunately, the old text so far will remain, as it is set by the WHO and is currently unchanged.


If two of the above factors are present, the patient meets the criteria for sepsis; however, what we commonly refer to as “sepsis” is actually severe sepsis and septic shock, meaning the infection has caused hypotension, hypoperfusion, and/or organ dysfunction.

The Swedish Infectious Diseases Association has developed guidelines for the assessment of severe sepsis and septic shock as follows. The changes should be caused by the systemic reaction and not be a direct effect of a local infection, and the changes should be new and not caused by another underlying disease. For the definition of severe sepsis to be met, the patient must have sepsis according to the above and one or more of the following criteria;

• Hypotension:
  • Systolic blood pressure <90 mm Hg
• Organ dysfunction:
  • Altered mental status; new-onset confusion, anxiety, aggression, or somnolence
  • Renal impairment; creatinine increase >45 μmol/L or oliguria, urine output < 0.5 ml/kg in at least 2 hours despite adequate fluid administration
  • Lung impairment: pO₂ <7.0 kPa on air (SO₂ approximately <86 %), pO₂ <5.6 kPa on air (SO₂ approximately <78 %) if the lung is the focus of infection
  • Coagulopathy; petechiae, ecchymosis, INR >1.5, a-APTT time >60 s, or PLT < 100
  • Liver impairment; s-bilirubin > 45 μmol/L.*
• Hypoperfusion:
  • Lactate >1 mmol above the upper reference value or BE ≤-5 mmol/L
  • decreased capillary refill, cold clammy skin, mottling.

*Intestinal impairment (absence of bowel sounds) is considered organ impairment in international guidelines, but not in the Swedish Infectious Diseases Association’s guidelines.

The often rapid and unpredictable course of severe sepsis emphasizes the importance of clear routines for monitoring vital parameters and set thresholds for contacting a doctor and ICU care. Most notably, during the first 24 hours after the onset of sepsis, patients are at risk of deterioration, justifying intensified monitoring and readiness to intervene during this period, to prevent the development of;

• Progressive severe sepsis: Deterioration of vital parameters or rising lactate during the observation period.
• Septic shock: Sepsis with hypotension despite adequate fluid therapy.



Epidemiology

Severe sepsis can affect anyone, but infants and the elderly are at increased risk, as are people with chronic diseases or weakened immune systems. Accurate prevalence data is lacking in Sweden, but it is estimated that 100–300 people per 100,000 per inhabitants are affected each year.

Preventive treatment

Appropriate treatment of infections requiring antibiotics without unnecessary delay is important to prevent progression to severe sepsis. The work with STRAMA guidelines is a good tool for outpatient doctors to prescribe antibiotics correctly. Overuse of antibiotics can risk creating conditions for the development of antibiotic resistance, which in turn can negatively impact outcomes in severe sepsis. For more information on STRAMA’s guidelines for outpatient care; link

General vaccination programs are important in preventing the development of certain serious infectious diseases. Annual influenza vaccination of risk groups should be emphasized as an important measure to prevent secondary sepsis cases, as well as pneumococcal vaccination according to given recommendations. Immunosuppressed patients are particularly vulnerable, and it is therefore important that these patients, in the event of infection complications, meet with a doctor with the right competence to assess the sometimes vague symptoms that can precede or indicate a serious infection. It is also important to inform patients undergoing immunosuppressive treatment on how to act when signs of infection appear. Sometimes special vaccination may be indicated in cases of immunosuppression.

Symptoms, clinical findings, and early identification

Severe sepsis is a serious infection characterized by organ damage. Most patients with community-acquired severe sepsis and septic shock are classified as red or orange according to the emergency department’s triage system (RETTS) upon arrival at the emergency department; however, the initial picture can sometimes be difficult to interpret, and a variety of symptoms and clinical findings may occur, which can vary depending on the entry point of the infection, the infecting agent, and the patient’s age and comorbidities.

Patients with severe sepsis or septic shock often have a fever or a history of fever and one of the following; elevated heart rate >90/min, elevated respiratory rate >20/min, falling blood pressure, low saturation <90%, anxiety, and confusion, gastrointestinal symptoms such as abdominal pain, diarrhea, or vomiting. With typical symptoms and an acute onset with chills, high fever, and impaired general condition, it is easy to suspect severe sepsis, but many patients, especially the elderly, often present a more atypical picture with, for example, confusion as the only symptom of severe sepsis. It is important to always consider sepsis when examining a seriously ill patient with an unclear diagnosis.

Consider the following warning symptoms for severe infection:

V-BAS; Wakefulness/Blood pressure/Respiratory rate/Saturation or the 90/30/90 rule:

• Wakefulness; decreased/new-onset mental impairment
• Blood pressure systolic <90 mmHg
• Respiratory rate >30 breaths per minute
• Saturation <90%

Sepsis alarm

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For early identification, a sepsis alarm should be used, which involves a modified version of RETTS focusing on patients at risk of serious infection. RETTS (Rapid Emergency Triage and Treatment System) is the triage system used in many emergency departments across the country. RETTS is based on vital parameters (blood pressure, pulse, respiratory rate, wakefulness, and temperature) with specified thresholds to sort patients into the correct priority group. Red RETTS means that the patient’s oxygenation is below 90% despite oxygen therapy, respiratory rate is over 30 or under 8, blood pressure <90 mm Hg, pulse >130, or that the patient is having seizures or is unconscious.

Vital parameters should also include an ESS (Emergency Signs and Symptoms), in severe sepsis ESS 47 (infection, fever, localized infection) is added. ESS 51 should also be added (known adrenal insufficiency, immunodeficiency, or immunosuppression), which ultimately determines the patient’s priority.

A sepsis alarm is triggered in patients with red RETTS who have a fever or a history of fever. In these cases, the patient is triaged according to a special algorithm, and an infectious disease specialist/medical resident/emergency physician is immediately called to the emergency room upon the patient’s arrival.

By focusing early on patients who have or are at risk of severe sepsis, it is ensured that the patient receives appropriate antibiotics within 60 minutes after blood cultures 2+2 and that appropriate supportive care is initiated and continued with IV fluids and oxygen.

SOME POINTS TO KEEP IN MIND TO AVOID MISSING PATIENTS WITH SEVERE SEPSIS

• Fever (>38.0°C) is not always present, and ear thermometers are unreliable. Hypothermia (<36.0°C) can be a serious sign in severe sepsis.
• “Found on the floor” can be secondary to sepsis
• Sepsis-induced confusion can be mistaken for a stroke.
• Remember that gastrointestinal symptoms and flu-like conditions can be due to severe sepsis.
• CRP can be normal or only moderately elevated initially.
• Observe the skin – petechiae? Infected wounds?
• Note the reduced immune response in certain groups, e.g., patients with rheumatic systemic diseases, IBD, malignant tumors, transplanted patients, splenectomized patients, and patients with ongoing or recently completed treatment with immunomodulating drugs such as Prednisolone 15 mg or more, Methotrexate®, Remicade® (infliximab), Enbrel® (etanercept) cytostatics, and others.

Primary measures

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• Monitoring – follow blood pressure, pulse, saturation, wakefulness!
• Establish a peripheral IV line.
• Oxygen 2–5 liters on nasal cannula, >5 liters on mask, saturation target >93%. Be cautious in COPD! Inform the emergency department if the patient has COPD.
• Ringer’s acetate infusion, if BP <90 mm Hg give bolus dose 500–1,000 ml over 30 min, repeat until treatment target is reached, i.e., BP >90 mm Hg. Overall, at least 30 ml/kg IV should be given within 3 hours in severe sepsis with hypotension.
• Paracetamol is only given when the patient is clinically affected by the fever or in ongoing cerebral ischemia/seizure/cardiac ischemia.

Prehospital identification and management

• Suspected infection is generally identified using RETTS
• Vital parameters should also include ESS 47, which determines the patient’s priority. In some cases, ESS 51 (known adrenal insufficiency, immunodeficiency, or immunosuppression) should also be used.
• In addition to this analysis, the following criteria, which are signs of suspected severe infection, should be noted;

Fever (temp >38.0°C) or low temp (<36.0°C)/history of fever and any of the following symptoms/signs:

• Petechiae/rash
• Signs of infected skin/soft tissues/joints
• New-onset severe pain
• Cerebral impairment/severe headache
• Urinary tract symptoms (especially with concomitant urinary catheter)
• Central venous catheter or other invasive port with signs of infection

Epidemiology? Always ask about recent travel abroad!

Note that fever may be absent in immunosuppressed patients and in patients who have taken paracetamol and NSAIDs, and that diarrhea/abdominal pain/vomiting are common symptoms in severe sepsis.

• Oxygen, adjusted according to saturation, 2–5 liters on nasal cannula, >5 liters on mask, saturation target >93%. Be cautious in COPD! Inform the emergency department if the patient has COPD.
• Establish a peripheral IV line.
• Consider intraosseous access if there is difficulty with a peripheral IV in critically ill patients who need immediate access for fluid/medication administration.
• Ringer’s acetate infusion, if BP <90 mm Hg bolus dose 500–1,000 ml over 30 min, repeat until treatment target is reached, i.e., BP >90 mm Hg. Overall, at least 30 ml/kg IV should be given within 3 hours in severe sepsis with hypotension.
• Refrain from routine administration of paracetamol for fever, antipyretics are only given when the patient is clinically affected by the fever or in ongoing cerebral ischemia/seizure/cardiac ischemia.

Intrahospital diagnostics and treatment

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• Initial management according to A – B – C – D – E
• Peripheral IV access x 2
• Consider a central venous catheter or intraosseous access if there is difficulty with peripheral IV access in critically ill patients who need immediate access for fluid/medication administration.
• Blood cultures 2+2
• Arterial or venous blood gas for lactate analysis.
• Blood tests; CRP, leukocytes, platelets, PT, APT time, liver function tests, urinalysis, blood glucose.
• Urine culture (urinary catheter if necessary) and other relevant cultures as ordered.
• Is there a suspected bacterial infection? Assess the infection focus. After appropriate cultures, decide on antibiotics according to point 15.
• In case of suspected meningitis, lumbar puncture, see national guidelines www.infektion.net
• ECG
• Consider bedside chest X-ray.
• Vital parameters every 5 minutes initially, until the patient stabilizes.
• Epidemiology? Always ask about recent travel abroad!
• Note that fever may be absent in immunosuppressed patients and in patients who have taken paracetamol and NSAIDs, and that diarrhea/abdominal pain/vomiting are common symptoms in severe sepsis.

Treatment of sepsis

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• The infectious disease specialist/medical resident/emergency physician* joins in the emergency room during a sepsis alarm, if an infectious disease specialist is not available at the hospital, consult the infectious disease specialist by phone for advice on investigation and antibiotic choice, especially in immunosuppressed patients and in patients suspected of carrying resistant bacteria.
• Oxygen, adjusted according to saturation, 1–5 liters on nasal cannula, > 5 liters on mask, treatment target >93%. Be cautious in COPD!
• Ringer’s acetate infusion, if BP <90 mm Hg bolus dose 500–1,000 ml over 30 min, repeat until treatment target BP >90 mm Hg. Overall, at least 30 ml/kg IV should be given within 3 hours in severe sepsis with hypotension or lactate >4.
• Choice of antibiotics is based on the severity of the infection and any suspected focus.

If antibiotics are prescribed, they should be administered without delay in the emergency department!

• Consider invasive management of the infection focus (so-called source control) in cases such as septic arthritis, abscess, obstructed pyelonephritis, empyema, bowel perforation, gynecological infection, or necrotizing fasciitis.
• If the patient is on or has recently completed corticosteroid treatment, administer Solucortef 100 mg IV.
• Urinary catheter – attach a system for hourly urine output, target level 0.5 ml/kg/hour.
• Administer Albumin 20% 100 ml if hypotension persists after 2–3 liters of Ringer’s acetate, do not use starch preparations (e.g., Voluven), if Albumin is not available, continue with Ringer’s acetate.
• Refrain from routine administration of paracetamol for fever. Antipyretics are only given when the patient is clinically affected by the fever or in ongoing cerebral ischemia/seizure/cardiac ischemia.

*Which on-call physician is called depends on the hospital; at hospitals with an infectious disease specialist on call, they should be called/consulted, otherwise, the medical resident or emergency physician according to local guidelines.

Level of care – admission

• Decision on the level of care; intensive care unit/intermediate care or ward.
• Transfer to the infectious disease ward, acute care ward, or another ward with sufficient monitoring resources without delay, during the waiting time to the ward, monitor vital parameters every 15 minutes.
• Assess whether there is a reason for treatment limitation.

Emergency room – continued deterioration of vital functions after initial measures

Establish contact with the medical emergency team or ICU on-call (infectious disease specialist) for consideration of ICU care.

• If BP <90 despite IV fluids or saturation <90 despite oxygen
• If lactate >4 or rising
• If RR >30 despite treatment
• In case of severe organ dysfunction such as decreased consciousness

Investigation and management

• Peripheral IV access x 2
• Blood cultures 2+2
• Arterial or venous blood gas for lactate analysis, if >3.5 the patient should be upgraded to red RETTS and a sepsis alarm triggered, see above.
• Blood tests; CRP, WBC, platelets, PT, APT time, liver function tests, urinalysis, blood glucose
• Urine culture (urinary catheter if necessary) and other relevant cultures as ordered.
• Is there a suspected bacterial infection? Assess the infection focus. After appropriate cultures, decide on antibiotics according to point 15.
• In case of suspected meningitis, lumbar puncture, see national guidelines www.infektion.net
• Vital parameters and supervision every 15 minutes.
• Epidemiology? Always ask about recent travel abroad!
• Note that fever may be absent in immunosuppressed patients and in patients who have taken paracetamol and NSAIDs, and that diarrhea/abdominal pain/vomiting are common symptoms in severe sepsis.

Treatment

• During the day, preferably handled by the day-duty infection specialist*, during on-call hours, consult the infection specialist by phone as needed to assess the patient in the emergency department, especially in immunosuppressed patients and in patients known to carry resistant bacteria.
• Oxygen, adjusted according to saturation, 1–5 liters on nasal cannula, > 5 liters on mask, treatment target >93%. Be cautious in COPD!
• Ringer’s acetate infusion 1,000 ml, overall, at least 30 ml/kg IV should be given within 3 hours in severe sepsis with hypotension or lactate >4.
• Choice of antibiotics is based on the severity of the infection and any suspected focus.

If antibiotics are prescribed, they should be administered without delay in the emergency department!

• Consider invasive management of the infection focus (so-called source control) in cases such as septic arthritis, abscess, obstructed pyelonephritis, empyema, bowel perforation, gynecological infection, or necrotizing fasciitis.
• If the patient is on or has recently completed corticosteroid treatment, administer Solucortef 100 mg IV.
• Antipyretics are only given when the patient is clinically affected by the fever or in ongoing cerebral ischemia/seizure/cardiac ischemia, refrain from routine administration for fever.

*Which on-call physician is called depends on the hospital; at hospitals with an infectious disease specialist on call, they should be called/consulted, otherwise, the medical resident or emergency physician according to local guidelines.

Antibiotic treatment in intensive care

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NOTE! Always take a culture sample from relevant sites before starting antibiotic treatment, such as blood, sputum, wound, and urine.


Investigation and Diagnostics of Severe Infections

Source	Unknown focus	Pneumonia	Abdominal infection	Acute bacterial meningitis
Cultivation of:	• Peripheral blood • CVC + arterial blood • Urine/wound/saliva	• Peripheral blood • CVC + arterial blood • Tracheal mucosa/ saliva/NPH	• Peripheral blood • CVC + arterial blood	• Peripheral blood • CSF
Other microbiological diagnostics	• Betaglucan [risk of invasive candida: prolonged ICU care (> 10 days), neutropenia, intestinal perforation, CVVHD] as needed	• U-antigen pneumoc + Legionella • Airway block (virus-PCR) • Atypical bacterias (PCR) • TB-diagnostics • Pneumocystis-PCR + β-glukan as needed	• Betaglucan [risk of invasive candida: prolonged ICU care (> 10 days), neutropenia, intestinal perforation, CVVHD] as needed	• CSF-PCR (bacterieas) • HSV-1 PCR (diff - diagnosis herpes encephalitis)

Initial Antibiotic Treatment in Severe Infections

Source	Unknown Foci3	Pneumonia3	Abdominal Infection	Acute bacterial meningitis
Community Acquired Infection	a. Pip/Taz 4g x 3-41 b. Cefotaxime 2g x 3 c. Meropenem 1g x 3-41 +/- aminoglycoside2	a. Cefotaxime 2g x 3 + Erythromycin 1g x 3 b. Phenoxymethyl-PcV 3g x 4 + Moxifloxacine 400mg x 1	a. Pip/Taz 4g x 3-41 b. Cefotaxime 2g x 3 + Metronidazol 1,5g x 1 c. Meropenem 1g x 3-41 +/- Aminoglycoside2	Meropenem 2g x 3 + Betametason 8mg x 4
Nosocomial Infection (>48 hours. after arrival to hospital)	a. Pip/Taz 4g x 3-41 b. Meropenem 1g x 3-41 +/- Vancomycin3 +/- Aminoglycoside2	a. Pip/Taz 4g x 3-41 b. Meropenem 1g x 3-41 +/- Aminoglycoside2	a. Pip/Taz 4g x 3-41 b. Meropenem 1g x 3-41 +/- Aminoglycoside2	Meropenem 2g x 3 + Vancomycin 15mg/kg x 3
Neutropenia (neutrofiles ≤ 0,5)	a. Meropenem 1g x 4 b. Pip/Taz 4g x 4 +/- Aminoglycoside2	a. Pip/Taz 4g x 4 + Moxifloxacine 400 mg x 1 b. Meropenem 1g x 4 + Moxifloxacine 400mg x 1	a. Meropenem 1g x 4 b. Pip/Taz 4g x 4 +/- Aminoglycoside2	Meropenem 2g x 3 + Betametason 8mg x 4
Severe allergy against beta-lactam antibiotics (anaphylactic shock, swelling/obstruction of respiratory tract)	Clindamycin 600 mg x 3-4 + Ciprofloxacin 400 mg x 3 +/- Aminoglycoside2	a. Clindamycin 600 mg x 3-4 + Moxifloxacine 400 mg x 1 b. Clindamycin 600 mg x 3-4 + Ciprofloxacin 400 mg x 3 (at hospitalized infection/suspicion of pseudomonas)	Clindamycin 600 mg x 3-4 + Ciprofloxacin 400 mg x 3 +/- Aminoglycoside2	a. Meropenem 2g x 3 (not in the case of shock due to beta-lactam antibiotics) b. Moxifloxacin + Vancomycin 15mg/kg x 3 + Trim/Sulphoxazine 20 ml x 2 (in the case of shock due to beta-lactam antibiotics)
Please consider carefully	• Rec. for "Unknown focus" includes urinary focus • Necrotising soft tissue infection (Fasciitis): Meropenem 1g x 4 + Clindamycin 600 mg x 3-4 + possible. iv immunoglobuline (GAS/S. aureus) • Endocarditis in cardiac valve disease or heart murmurs • Malaria: Africa/Asia	• Legionella: international travel, immunosuppression, chronic lung disease • Pneumocystis/aspergillus: immunosuppression • Tuberculosis: origin, age, immunosuppression, addiction, long-term progression • Influenza: Oseltamivir (Tamiflu®) 75 mg x 2 p.o. + Cefotaxime 2 g x 3	• Early "source control" • Invasive candida: prolonged ICU care, neutropenia, intestinal perforation, CVVHD Fluconazole i.v. 800 mg x 1 day 1, then 400 mg x 1, at sepsis Micafungine 100 mg x 1	• TB meningitis: descent • Fungal meningitis: immune suppression • Herpes encephalitis: focal symptom Acyclovir 10 mg/kg x 3
Serious and complicated infections should be assessed by infection consultant/back-up within 24 hours or no later than next weekday.
1Betalactam antibiotics: As a result of increased volume of distribution, high and frequent doses should always be given (Pip/Taz 4g x 4, Cefotaxime 2g x 3, meropenem 1g x 4). In addition, provide an additional loading dose of selected beta-lactam antibiotic approximately 3 hours after the first dose. As the condition stabilizes, the usual dose of beta-lactam antibiotics should generally be given.
2Supplementary therapy with aminoglycoside should always be considered during sepsis and septic shock (Sepsis-3) if the infection can be caused by gram-negative bacteria (unknown focus, urosepsis, abdominal infection, VAP). Tobramycin (Nebcin©) is given at a dose of 7 mg/kg x 1. In case of obesity, the dose should be based on estimated ideal body weight. In case of increased risk of ESBL bacteria (ESBL infection, overseas care, stay in an ESBL endemic country last 6 months or treatment with cephalosporines/kinolones last 3 months) instead, amicacine is given because ESBL bacteria are often resistant to tobramycine too. Amicacin (Biklin©) is given in the dose of 25 mg/kg x 1 with dose adjustment in obese patients as above. Often enough a dose of aminoglycoside but any continued dose is controlled by conc. determination after 24 hours (lowest value).
3Supplementary treatment with Vancomycin 15 mg/kg x 3 should be considered in the known carrier of MRSA (not in urinary tract focus) and in suspected care-related KNS infection. Concentration determination before the 4th dose (lowest value). On the basis of the resistance pattern, in some cases you can choose other antibiotics.
Patient with renal failure/dialysis: The first treatment week should be done with beta-lactam antibiotics as in normal renal function. For continued dosing during dialysis, see national guidelines information at:Click here!




Antibiotic Therapy according to Diagnosis and Alternative Therapy when Penicillin Allergy

Diagnosis	Therapy	Alternative Therapy for PcV allergy
Pneumonia	Inj. Phenoxymethylpenicilline (Penicilline V) 1 g x 3 i.v. (also with COPD) or T. Penicilline V 1 g x 3 or T. Amoxicillin 500 mg x 3 (patients with COPD)	Inf. Erythromycin (Abboticin) 1 g x 3 i.v. or T. Eryhtromycin 500 mg x 2 or. T. Doxycycline 100 mg x 1 (at COPD; double dose the first day)
Pyelonephritis/Febrile Urinary Tract Infection	Inj. Tobramycin (Nebcin*) 4,5 mg/kg x 1 i.v. alt. Inj. Cefotaxime 1 g x 3 i.v. alt. T. Ciprofloxacin 500 mg x 2	Inj. Tobramycin (Nebcin*) 4,5 mg/kg x 1 i.v.
Acute Cystitis	T. Nitrofurantoin (Macrobid) 50 mg x 3 alt. T. Pivmecillinam 200 mg x 3
Erysipelas (Streptococcus)	Inj. Phenoxymethylpenicilline (Penicilline V) 1-3 g x 3 i.v. alt. T. Penicilline V 1 g x 3	Inf. Clindamycin 300 mg x 3 i.v. alt. C. Clindamycin 300 mg x 2-3
Skin and soft tissue infection (S. aureus)	Inf. Cloxacillin 2 g x 3 i.v. alt. T. Flucloxacillin 1 g x 3	Inf. Clindamycin 300 mg x 3 i.v. alt. C. Clindamycin 300 mg x 2-3
Abdominal infection	Inj. Piperacillin/Tazobactam 4 g x 3 i.v. alt. Inj. Cefotaxime 1 g x 3 i.v. + Inf. Metronidazole 1 g x 1 i.v. alt. Inj. Meropenem (Merrem) 0,5 g x 3 i.v. (in case of severe, complicated infection)	Inf. Ciprofloxacin 400 mg x 2 i.v. + Inf. Clindamycin 600 mg x 3 i.v.
Severe bacterial infection of unknown origen	Inj. Phenoxymethylpenicilline (Penicilline V) 1 g x 3 i.v. + Inj. Tobramycin (Nebcin*) 4,5 mg/kg x 1 i.v. alt. Inj. Cefotaxime 1 g x 3 i.v.	Inj. Tobramycin (Nebcin*) 4,5 mg/kg x 1 i.v. + Inf. Clindamycin 600 mg x 3 i.v.

Community Acquired Infection with Severe Sepsis or Septic Shock

Infection	Suggestion of Antibiotics
Sepsis of unknown origen	A) Piperacilline/Tazobactam 4 g x 4 + Tobramycin (Nebcin®) 5-7 mg/kg x 1 B) Meropenem 1 g x 4 + Tobramycin (Nebcin®) 5-7 mg/kg x 1
Pneumonia	A) Cephotaxime 1 g x 3 + Erythromycin (Abboticin®) 1 g x 3 + Tobramycin (Nebcin®) 5-7 mg/kg x 1 B) Phenoxymethylpenicilline 3 g x 4 + Moxifloxacin (Avelox®) 400 mg x 1 + Tobramycin (Nebcin®) 5-7 mg/kg x 1
Abdominal infection	A) Piperacillin/Tazobactam 4 g x 3 + Tobramycin (Nebcin®) 5-7 mg/kg x 1 B) Meropenem 1 g x 4 + Tobramycin (Nebcin®) 5-7 mg/kg x 1
Fasciitis/myositis	A) Meropenem 1 g x 4 (alt. Phenoxymethylpenicilline 3 g x 4 with verified grp A strpc) + Clindamycin 600 mg x 3 + Tobramycin 5-7 mg/kg x 1 (not with Strpc A)
Meningitis	Meropenem 2 g x 3

Community Acquired Infection without Severe Sepsis or Septic Shock

Infection	Choice of Antibiotics
Sepsis of unknown origen	Piperacillin/Tazobactam 4 g x 3-4
Pneumonia	A) Cephotaxime 1 g x 3 + Erythromycin (Abboticin®) 1 g x 3 B) Phenoxymethylpenicilline 3 g x 4 + Moxifloxacin (Avelox®) 400 mg x 1 +
Abdominal infection	A) Piperacillin/Tazobactam 4 g x 3 B) Cephotaxime 1 g x 3 + Metronidazol 1.5 g x 1 C) Meropenem 0.5 g x 3
Fasciitis/myositis	Meropenem 1 g x 4 (alt. Phenoxymethylpenicilline 3 g x 4 at verif group A strpcocc) + Clindamycin 600 mg x 3
Meningitis	Meropenem 2 g x 3

Nosocomial Infection Hospital Acquired (> 48 hours in hospital)

Infection	Choice of Antibiotics
Sepsis of unknown origen	A) Meropenem 0,5-1 g x 3-4 + ev. Tobramycin (Nebcin®) 5-7 mg/kg x 1 B) Piperacillin/Tazobactam 4 g x 3 + ev. Tobramycin (Nebcin®) 5-7 mg/kg x 1
Pneumonia	A) Piperacillin/Tazobactam 4 g x 3-4 + ev. Tobramycin (Nebcin®) 5-7 mg/kg x 1 B) Meropenem 0,5-1 g x 3-4 + ev. Tobramycin (Nebcin®) 5-7 mg/kg x 1
Abdominal infection	A) Piperacillin/Tazobactam 4 g x 3-4 + ev. Tobramycin (Nebcin®) 5-7 mg/kg x 1 B) Meropenem 0,5-1 g x 3-4 + ev. Tobramycin (Nebcin®) 5-7 mg/kg
Fasciitis/myositis	Meropenem 1 g x 3-4 + ev. Tobramycin (Nebcin®) 5-7 mg/kg
Meningitis	Meropenem 2 g x 3 + Vancomycin 1 g x 3 (after Neurosurgery)

Immune Deficiency Patients with Neutropenia

Infection	Choice of Antibiotics
Sepsis of unknown origen	A) Meropenem 0,5-1 g x 4 + ev. Tobramycin (Nebcin®) 5-7 mg/kg B) Piperacillin/Tazobactam 4 g x 4 + ev. Tobramycin (Nebcin®) 5-7 mg/kg
Pneumonia	A) Meropenem 0,5-1 g x 4 + Erythromycin (Abboticin®) 1 g x 3 + ev. Tobramycin (Nebcin®) 5-7 mg/kg B) Piperacillin/Tazobactam 4 g x 4 + Erythromycin (Abboticin®) 1 g x 3 + ev. Tobramycin (Nebcin®) 5-7 mg/kg
Abdominal infection	A) Piperacillin/Tazobactam 4 g x 4 + ev. Tobramycin (Nebcin®) 5-7 mg/kg B) Meropenem 0,5-1 g x 4 + ev. Tobramycin (Nebcin®) 5-7 mg/kg
Fasciitis/myositis	Meropenem 1 g x 4 (alt. Phenoxymethylpenicilline 3 g x 4 at verif group A strpk) + Clindamycin 600 mg x 3
Meningitis	Meropenem 2 g x 3

Serious Penicillin Cefalosporin Allergy

Infection	Choice of Antibiotics
Sepsis of unknown origen	Clindamycin 600 mg x 3 + Ciprofloxacin 400 mg x 3 + Tobramycin (Nebcin®) 5-7 mg/kg
Pneumonia	Clindamycin 600 mg x 3 + Moxifloxacin (Avelox®) 400 mg x 1 (vid VAP Ciprofloxacin 400 mg x 3) + ev. Tobramycin (Nebcin®) 5-7 mg/kg
Abdominal infection	Clindamycin 600 mg x 3 + Ciprofloxacin 400 mg x 3 + ev. Tobramycin (Nebcin®) 5-7 mg/kg
Fasciitis/myositis	Clindamycin 600 mg x 3 + Ciprofloxacin 400 mg x 3 + ev. Tobramycin (Nebcin®) 5-7 mg/kg
Meningitis	A) Meropenem 2 g x 3 (not at anaphylactic shock of PcV) + Vancomycin 1 g x 3 B) Moxifloxacin (Avelox®) 400 mg x 1 + Vancomycin 1 g x 3 + Trimetoprim Sulfametoxazol 20 ml x 2

Antibiotic Selection in Severe Sepsis

Source of Infection	Antibiotic Choice
Suspected pneumonia	Cefotaxime 2 g + Tavanic 0,5 g
Suspected Urosepsis**	Cefotaxime 2 g + Amino Glycoside* 4,5-7 mg/kg
Suspected Abdominal Foci**	Piperacilline/Tazobactam 4 g/Meropenem 1 g/Imipenem 1 g + ev. Single Dose of Amino Glycoside* 4,5–7 mg/kg
Suspected skin/Soft tissue infection	Suspected Streptococcal genesis: Phenoxymethylpenicilline-pcV 3 g + Clindamycine 600 mg Suspected Staf. Aureus genesis Cloxacilline 2 g + Clindamycine 600 mg Suspected Fasciitis/Myositis Meropenem/Imipenem 1 g + Clindamycine 600 mg + ev. Amino Glycoside* 4,5–7 mg/kg
Suspected meningitis	Cefotaxime 3 g + Ampicilline 3 g + Betametason
Unknown Foci**	Piperacilline/Tazobactam 4 g/Meropenem 1 g/Imipenem 1 g + Amino Glycoside* 4,5–7 mg/kg. In a stable patient with rapid transient organ failure, treatment with Cefotaxime 2 g + Amino Glycoside* 4.5 mg/kg may be considered.
Unknown foci and Type 1 hypersensitivity to Penicilline	Clindamycine 600 mg + Ciprofloxacin 400 mg + Hypersensitivity to penicillin: a dose Amino Glycoside* 4,5–7 mg/kg

Antibiotic Selection in Moderate Sepsis without Organ Failure

Source of Infection	Antibiotic Choice
With unknown origen	Phenoxymethylpenicillin 1-3 g + Amino Glycoside 4.5 mg/kg alternatively Cefotaxime 1 g if risk factors for Amino Glycoside related side effects are known as known hearing loss or chronic renal impairment.
With suspected focus; for example pneumonia, febrile UVI / pyelonephritis, erysipelas.	Antibiotic treatment in accordance with local guidelines or STRAMA Guidelines for infections in hospitalized patients.

In severe sepsis, add aminoglycoside (tobramycin – Nebcina) on the first day at a dose of 5-7 mg/kg ×1 if creatinine clearance >80; 4.5-2.2 mg/kg×1 if creatinine clearance 80-41; 2.2-1 mg/kg×1 if creatinine clearance 40-20; weight ~ lean body mass. Serum concentration of tobramycin, given once daily, is determined 8 hours after the dose and should be 1.5-4.0 mg/L.

The dosing instructions assume an adult patient with normal kidney function. Creatinine clearance (ml/min) = F x (140-age) x weight/S-creatinine; F≈1.2 for men; F≈1.0 for women.

In cases of increased risk for ESBL-producing intestinal bacteria (travel abroad, foreign hospitalization, known carriage): Meropenem 1g x 4 + amikacin (Biklin) 20-25 mg/kg x 1. In cases of fasciitis/myositis, contact the infectious disease specialist for consideration of possible IV immunoglobulin. In cases of meningitis, always add treatment with betamethasone (Betapred) 8 mg x 4.

Higher doses and more frequent dosing in severe sepsis/septic shock due to increased distribution volume and impaired microcirculation. Usually lower/less frequent dosing later in the course. Add Nebcina 1 dose/day in severe sepsis/septic shock. Standard dose 7 mg/kg. Lower dose (5 mg/kg) in advanced age or chronic renal failure. Avoid Nebcina if GFR < 20 ml/min. When treating with Biklin, measure trough concentration, i.e., immediately before the next dose.

Fungal infections in intensive care

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Fungal infections and fungal sepsis are common in intensive care, especially in patients receiving prolonged broad-spectrum antibiotic therapy, immunosuppressed patients, generally debilitated patients with poor nutritional status, or patients with extensive necrosis or burns. Therefore, adding antifungal agents is common in treating intensive care patients. The presence of deep fungal infection can be confirmed with beta-glucan testing. Beta-glucan is a fungal antigen that can be detected in the blood during invasive fungal infection. Values over 100 pg/mL are considered positive, and values under 100 pg/mL are negative. However, beta-glucan does not react against mucormycosis, cryptococcus, or blastomyces. Treatment for invasive fungal infection typically needs to continue for an extended period. The recommended treatment duration is at least 2 weeks after the first negative test. Sometimes treatment is required for 1-3 months.

Here are some simple mnemonic rules for antifungal treatment in invasive fungal infection.

• Fluconazole (Diflucan, Fluconazole) – for treating candida albicans infections

Dosage: 800 mg day 1. Subsequent dose: 400 mg once daily

• Cancidas (Caspofungin) – for candida glabrata or resistance to Fluconazole

Dosage: A 70 mg loading dose should be administered on day 1, followed by 50 mg daily. For patients weighing more than 80 kg, after the initial 70 mg loading dose, 70 mg daily is recommended

• Vfend (Voriconazole) – for invasive aspergillosis

Dosage: Loading dose: 400 mg every 12 hours on the first day, then 200 mg every 12 hours

• Mycamine (Micafungin) – like Cancidas: invasive candidiasis

Dosage: 100 mg/day

• Noxafil (Posaconazole) – administered orally/parenterally. Invasive aspergillus infection.

Dosage: 300 mg x 2 on day 1. Subsequent dose: 300 mg once daily

• Ecalta (Anidulafungin) – primarily for liver or kidney failure. Invasive candidiasis.

Dosage: A starting dose of 200 mg should be given on day 1, followed by 100 mg per day thereafter.

• Cresemba (Isavuconazonium) – invasive aspergillosis, mucormycosis.

Dosage: 200 mg x 3 should be given on days 1-2, followed by 200 mg per day thereafter.

• AmBisome (Amphotericin B) –  severe systemic and deep fungal infections.

AmBisome liposomal should be given as an intravenous infusion over 30-60 minutes. Start treatment with 3 to 5 mg/kg, administered daily for at least 14 days.

Sedation of ICU Patients

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Sedation of intensive care patients is provided according to the patient’s need for anxiety relief and pain management, and it is tailored to ongoing medical treatments and procedures. Sedation is generally administered as a continuous intravenous infusion of two separate drugs in parallel. Sedation is routinely given to patients on mechanical ventilation to tolerate the tube and follow respiratory ventilation. An oral tube is very difficult to tolerate without sedation. A tracheal cannula is less irritating than a nasal tube, which is less irritating than an orally placed tube.

Common drugs administered to patients on mechanical ventilation include propofol plus remifentanil or propofol plus fentanyl in continuous infusion. Sedation can also be administered as an inhalation agent via ventilator or as intermittent bolus doses. Continuous infusions are primarily given to patients on mechanical ventilation, while patients without a ventilator usually receive intermittent doses of medication, such as morphine.

Sedation should allow for mobilization even of intubated patients and is always tailored to the need for pain relief and circadian rhythm. The goal is to allow the patient to be awake, mobilized, and pain-free with a normal circadian rhythm and functioning natural functions.

Medications and depth of sedation are administered with consideration of:

• Alertness (graded according to MAAS, SAS, or RASS)
• Pain
• Anxiety, possibly delirium
• Patient comfort
• Mobilization
• Mechanical ventilation and respiratory ability
• Surgical wounds, drains, catheters, tubes, IV lines, etc.
• Minimizing circulatory and respiratory stress
• Care needs, dressings
• Natural functions, gastrointestinal function, kidney function – diuresis
• Circulation and circulatory impact
• Intracranial pressure – ICP
• Circadian rhythm
• “WUC” – wake up call
• Waking and extubation

Before waking and extubation, it is common to reduce (or pause) the propofol infusion while maintaining a low dose of opioid to allow awakening without excessive discomfort. It is usually possible to extubate with continued infusion of a low dose of fentanyl or remifentanil. Abrupt cessation of remifentanil can lead to too rapid awakening with pain and high stress levels in connection with extubation. Additionally, abrupt awakening can make it difficult to assess the patient’s ability to breathe independently. Before discontinuing remifentanil during extubation, it may be appropriate to administer, for example, 5-10 mg of morphine or oxycodone intravenously. Before extubation, the patient should be able to look up, make contact, and breathe calmly on their own.

Sedation of adults on a ventilator

Drugs	Infusion dose	Concentration	Caution
Propofol	1 - 4 mg/kg/h	20 mg/ml	Bolus dose: 1 - 3 mg/kg
Fentanyl	0,5 - 2 μg/kg/h	50 μg/ml	Higher doses may need to be given. Maximal dose 6 μg/kg/h
Remifentanil	0,05 - 0,25 μg/kg/min	50 μg/ml	May cause hyperalgesia
Dexmedetomidine	0,4 - 1,4 μg/kg/h	8 μg/ml	Starting dose usually 0.7 μg/kg/h. Treatment time max 2 weeks. OBS bradycardia, hyperthermia
Clonidine	0,5 - 2 μg/kg/h	15 μg/ml
Midazolam	0,05 - 0,2 mg/kg/h	5 mg/ml	Bolus dose: 0,05 - 0,1 mg/kg
Morphine	5 - 30 μg/kg/h	1 mg/ml	Bolus dose: 0,05 - 0,1 mg/kg

Medications for Sedation of ICU Patient

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Propofol

Brand names: Diprivan^®, Propolipid^®, Recofol^®, Propofol

Intravenous anesthetic 20 mg/ml. Dosage: 1-3 mg/kg/hour (2-15 ml/hour, 20 mg/ml). Common dose 5-7 ml/h.

Fentanyl

• Brand names: Fentanyl^®, Leptanal^®

Intravenous anesthetic and analgesic. Solution: 0.05 mg/ml, 50 μg/ml. Dosage: For sedation of ICU patients, the usual dosage is 1-2-(4) ml fentanyl intravenously per hour.

Midazolam

• Brand names: Midazolam^®

Intravenous sedative and anxiolytic benzodiazepine. Common strength is 1 mg/ml or 5 mg/ml. Dosage: 1-5 ml/h, 1-25 mg/h. Common dose 2-3 ml/h.

Remifentanil (Ultiva^®)

Intravenous short-acting opioid for sedation of ICU patients. Solution 50 μg/ml. Recommended concentration for sedation of adults in continuous infusion is 0.05 mg/ml (50 μg/ml). Dosage: 0.05-0.20 μg/kg/min (1-6 ml/hour) at a concentration of 0.05 mg/ml.

Alfentanil (Rapifen^®)

Intravenous sedative and analgesic. Solution 0.5 mg/ml. Dosage: 0.5-3 mg/hour (1-6 ml/hour), at a concentration of 0.5 mg/ml.

Dexmedetomidin (Dexdor^®)

Sympatholytic. Central alpha₂-agonist. Provides sedation, lowers heart rate, reduces blood pressure, and lessens stress response. Dexmedetomidin is the S-enantiomer of medetomidine. Dosage: In continuous infusion 0.2-1.4 µg/kg/h. Suitable starting dose is around 0.7 µg/kg/h for sedation. Solution 100 µg/ml. For continuous infusion, dilute to 4 µg/ml or 8 µg/ml.

Comparison of three of the commonly used sedation scores

Sedation score by Ready et al.	Pasero opioid-induced sedation scale	Sedation score recommended by ANZCA FPM
0 (none) alert	S = Sleep, easily aroused	0 = wide awake
1 (mild) occasionally drowsy, easy to arouse	1 = Awake and alert	1 = easy to rouse (and can stay awake)
2 (moderate) frequently drowsy; easy to arouse	2 = Occasionally drowsy	2 = easy to rouse but unable to remainawake
3 (severe) somnolent, difficult to arouse	3 = Frequently drowsy, arousable, drifts off to sleep difficult to arouse during conversation.	3 = difficult to rouse Score of 2 = early opioid-inducedventilatory impairment. Titrate opioid so that score is always < 2.
S (sleeping) normal sleep, easy to arouse	4 = Somnolent, minimal or noresponse to stimulation. Subsequently updated, and nowaccompanied by instructions outlining appropriate actions
ANZCA FPM, Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine

MAAS (Motor Activity Assessment Scale)

MAAS (Motor Activity Assessment Scale) is documented every 3 hours in patients treated with a ventilator or with CPAP/non-invasive ventilation or spontaneous breathing on a tube/trach.

MAAS-Scale

0:	Unresponsive
1:	Responsive only to noxious stimuli
2:	Responsive to touch or name
3:	Calm and Cooperative
4:	Restless and cooperative
5:	Agitated
6:	Dangerously agitated, uncooperative

Richmond Agitation-Sedation Scale (RASS)

Richmond Agitation Sedation Scale RASS

+4	Combative	Overtly combative or violent; immediate danger to staff
+3	Very agitated	Pulls on or removes tube(s) or catheter(s) or has aggressive behavior toward staff
+2	Agitated	Frequent nonpurposeful movement or patient–ventilator dyssynchrony
+1	Restless	Anxious or apprehensive but movements not aggressive or vigorous
±0	Alert and calm	Spontaneously pays attention to caregiver
-1	Drowsy	Not fully alert, but has sustained (more than 10 seconds) awakening, with eye contact, to voice
-2	Light sedation	Briefly (less than 10 seconds) awakens with eye contact to voice
-3	Moderate sedation	Any movement (but no eye contact) to voice
-4	Deep sedation	No response to voice, but any movement to physical stimulation
-5	Unarousable	No response to voice or physical stimulation

Different MAAS levels or RASS levels are requested for different patients. Increased sedation (low number) may increase the risk of respiratory and circulatory complications, while patient safety sometimes requires it.

Patient comfort at different levels of sedation is still relatively unknown. New findings suggest that patients who can clearly remember their intensive care have fewer unpleasant memories (hallucinations, nightmares, paranoid delusions) than those who do not remember as well. The RACHEL study found that patients who were kept deeply sedated for longer periods were more affected by hallucinations and nightmares.

Goal-Related Sedation

A desired MAAS level or RASS level should be determined daily for each individual patient after discussion within the care team. Usually MAAS 2 or 3. The physician prescribes an appropriate MAAS, e.g., 2. If the patient is then noted to correspond to MAAS 1, the nurse turns off the sedative medication until the patient returns to MAAS 2, after which sedation is restarted at a lower rate than before.

Sedatives for Intensive Care Patients

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Remifentanil (Ultiva) 50 μg/ml IV

• Indication: For sedation > 3 days as well as for conditions like renal or liver failure & obesity
• Dosage: 0.025-0.25 μg/kg/min. For pain procedures: 0.25 – max 0.75 μg/kg/h

Propofol 10 mg/ml, 20 mg/ml IV

• Maintenance for sedation: 0.1-4 mg/kg/h, only for patients > 16 years old

Fentanyl 50 μg/ml IV

• Maintenance dose for sedation in ICU:
  • Adults 0.5-2 μg/kg/hour
  • Children: 0.5-1 μg/kg/hour
• Standard dose: 0.5 μg/kg/h

In ventilated patients, a loading dose of fentanyl can be administered as a rapid infusion of approximately 1 μg/kg/minute over the first 10 minutes, followed by an infusion of approximately 0.5 μg/kg/hour. Alternatively, the loading dose of fentanyl can be administered as a bolus dose. The infusion rate should be titrated according to individual patient response; lower infusion rates may be sufficient.

Midazolam 1 mg/ml, 5 mg/ml IV

• Benzodiazepine. Effect within 2 min – max effect 5-10 min
• Dosage: Bolus adult 0.5-2 mg IV Bolus for children: 0.05-0.1 mg/kg
• Infusion: 0.1-0.3 mg/kg/h, 1-25 mg/h
• Intramuscular: 5-10 mg (5 mg/ml)

Dexdor 8 μg/ml IV (dexmedetomidine)

• α1-α2 agonist 1:1620
• t_1⁄2 = 2 h
• Dosage: If circulatory stable, bolus 1 μg/kg over 10 min. Maintenance infusion: 0.2-1.4 μg/kg/h
• Contraindication: AV-block II-III, pregnancy, pronounced hypovolemia, combination with clonidine

Catapresan (clonidine)

• α1-α2 1:200 agonist, parenteral = enteral dose, t_1⁄2=8 h – longer with continuous infusion
• Dosage: Infusion: max 0.33 μg/kg/h or 75-150 μg x 4. Same dose orally.
• Contraindication: bradycardia, SSS, AV-block II-III, combination with Dexmedetomidine, severe hypotension

Propavan tablet 25 mg (propiomazine)

• Dosage: 1-2 tablets no later than 20:00.
• t_1⁄2 = 8 h

Imovane (zopiclone) tablet 5/7.5 mg

• Dosage: 1 tablet at night, given before 02:00. Max 15 mg.

Haldol 5 mg/ml IV (haloperidol)

• Low-dose neuroleptic, dopamine blocker
• t_1⁄2 = 19 h
• Dosage: 1-5 mg IV, 2.5-5 mg x 4 may be tried. Dose reduction in liver failure
• Caution: Parkinson’s, long QT syndrome, hypokalemia, extrapyramidal side effects

Nutritional Calculator

Follow the link to access the nutritional calculator.



Heparin Regimen for Thromboembolic Events

Heparin, which naturally occurs in the body bound to protein, is a strongly acidic, sulfated glycosaminoglycan (mucopolysaccharide) with anticoagulant effect. In combination with the co-factor antithrombin III, heparin affects several steps in the coagulation mechanism, providing a blood-thinning effect. Heparin is used in the treatment of thromboembolic events such as pulmonary embolism or deep vein thrombosis.

Dosage

• For the treatment of deep vein thrombosis, a bolus dose of 5000 IU (1 ml) is given intravenously for patients weighing under 85 kg.
• For those weighing over 85 kg, a bolus of 7500 IU (1.5 ml) is given intravenously.
• For the treatment of pulmonary embolism, a bolus of 7500 IU (1.5 ml) is given intravenously.
• In massive DVT/PE: a larger bolus (100-150 IU/kg) is administered.
• If there is an increased risk of bleeding, a bolus of 2500 IU is given intravenously, except in the case of massive pulmonary embolism/DVT. If pulmonary embolism is suspected, a bolus and infusion are given while awaiting diagnosis. Thereafter, a continuous infusion of heparin is administered. 15000 IU (3 ml) is added to 500 ml of 0.9% NaCl or 7500 IU (1.5 ml) in 250 ml of 0.9% NaCl. The infusion starts simultaneously with the bolus dose.
• For patients weighing > 60 kg and under the age of < 65 years, 42 ml/hour is administered. For other adults, 36 ml/hour is given. The treatment effect is monitored with APTT controls. The first APTT control is after 6 hours. APTT should be 1.5-3 times the reference value, i.e., 60-120 seconds (in cases of increased bleeding risk, 50-80 seconds).

Heparin Dosing Schedule

Correction measurements according to APTT values

aPTT value without increased bleeding risk (target value 60-120 sec)	aPTT value at increased bleeding risk (target value 50-80 sec)	Primary action	Adjust the drop rate	New sample checked
> 200 sec	>160 sec	Check the infusion mixture. Take a new test APTT sample, turn off the drop for 1 hour (not the first APTT after drip start)	Reduce at 9 ml/h	New test after 4 hours
181-200 sec	141-160 sec		Reduce at 9 ml/h	New test after 6 hours
141-180 sec	111-140 sec		Reduce at 6 ml/h	New test after 6 hours
121-140 sec	81-110 sec		Reduce at 3 ml/h	New test after 6 hours
60-120 sec	50-80 sec		Unchanged infusion rate	If the first value after drip start, take a new test after 6 hours, or after 12 hours.
50-59 sec	40-49 sec		Increase at 2 drops/min (= 6 ml/h)	New test after 6 hours
< 50 sec	< 40 sec	Give 2500 E of Heparin i.v. and	Increase infusion rate at 9 ml/h	New test after 6 hours

Indication

Anticoagulation. Deep vein thrombosis (DVT), pulmonary embolism. Intravascular coagulation, peritendinitis crepitans. Extracorporeal circulation in connection with cardiac surgery and hemodialysis.

Side Effects

Bleeding, thrombocytopenia, transient liver impairment.

Concentration

5000 IU/ml, 25 000 IU/ml.

Warning

Heparin is contraindicated when there is a high risk of bleeding. Caution is recommended in cases of thrombocytopenia and platelet function defects (including drug-induced), as well as in severe liver and renal insufficiency.

Heparin-Induced Thrombocytopenia (HIT)

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Thrombocytopenia that occurs after prolonged heparin treatment, often in connection with sepsis treatment. It can be difficult to differentiate from sepsis-induced thrombocytopenia. The body forms antibodies against heparin. The condition is prothrombotic despite thrombocytopenia, which is why both bleeding and thrombosis can occur simultaneously. Thrombocytopenia may develop slowly after 5-7 days of treatment or suddenly after a bolus dose of heparin. Platelet count can be around 100 but also lower, down to 50.

Diagnosis is obtained through the assessment of HIT criteria (“Four T’s”) and testing that varies in different laboratories.

• HIT Elisa (immunological test)
• Aggregation test. The antibodies in the heparin–PF4 complex cause platelet activation.

In HIT, it is important to discontinue all heparin and instead administer Arixtra. Heparin should not be re-administered within 3-4 months.

Probability assessment for HIT type-II-four-T

"Four T's"	2 points	1	0
Thrombocytopenia	>50% platelet decrease, lowest value 20–100 × 10⁹/l	30–50% platelet decrease, lowest value 10–19 × 10⁹/l	<30% decrease, lowest value <10 × 10⁹/l
Time	Start day 5–10 or day 1 if previously exposed to heparin	Unclear start due to missing lab values or start after day 10	Start before day 5 without prior heparin exposure
Thrombosis	New thrombosis, skin necrosis, acute systemic reaction after intravenous heparin bolus	Progressive thrombosis or recurrent thrombosis. Suspected but not yet verified new thrombosis	No thrombosis
Thrombocytopenia due to another cause	No other cause found	Another possible cause exists	A definite other cause exists

Diabetes Mellitus, Perioperative Management

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Diabetes is divided into Type 1 diabetes and Type 2 diabetes. Type 1 diabetes is due to insufficient insulin production. Type 2 diabetes is usually due to poor metabolic control and insulin resistance.

Poorly regulated diabetes increases the risk of complications with poorer wound healing, higher infection risk, and the risk of hypoglycemia in connection with anesthesia and surgery. For elective procedures, normalized metabolic control should be aimed for.

HbA1c is a long-term measure of glucose level. The target value for HbA1c is 52 mmol/mol, which reduces the risk of complications. HbA1c is a form of hemoglobin (glycated hemoglobin) whose measurement provides an average of how blood sugar has been over a period of time (1-3 months). HbA1c is measured in mmol/mol.

If preoperatively, patients have P-Glucose above 15 mmol/L, this should be addressed before the operation. For emergency surgeries, normoglycemia is sought pre-, peri-, and postoperatively. If the patient is over 80 years old, it is advisable to avoid lowering blood sugar too much and, above all, to avoid hypoglycemia.

The target value for perioperative P-Glucose is 4-12 mmol/L.

There are several different types of insulin. Basal insulin usually refers to intermediate-acting or long-acting insulin. Mealtime insulin refers to rapid-acting or short-acting insulin.

Different Types of Insulin

Type of Insulin	Suggestion of Medication
Directly Acting Insulin	NovoRapid Humalog Apidra
Short-acting Insulin	Actrapid Humulin Regular Insuman Rapid
Intermediate-acting Insulin	Humulin NPH Insulatard Insuman Basal
Long-acting Insulin	Lantus Levemir Toujeo (glargin 300 E/ml) Tresiba Xultophy Abasaglar
Mixed Insulin	Lantus Humalog Mix 25 Humalog Mix 50 NovoMix 30

Short-Acting Insulin

Short-acting insulins are divided into human insulins (Actrapid and Humulin regular) and insulin analogs (Apidra, Humalog, and Novorapid).

• Human insulins start working within 30 minutes, have maximum effect after about 2 hours, and a total duration of 5-7 hours.
• Insulin analogs start working within 10-15 minutes, have their maximum effect after about 1 hour with a total duration of 3-4 hours.
• Due to the longer duration of action of human insulins, they are preferred over insulin analogs in the ICU and postoperative care.

Intermediate-Acting (NPH)

Intermediate-acting insulins (Humulin NPH, Insulatard, and Insulin basal) start working after 1-3 hours to reach maximum effect after 4-10 hours. The duration is 15-16 hours.

Long-Acting Analogs

1. Levemir has a duration of about 15-20 hours.
2. Lantus and Abasaglar have a duration of about 20-28 hours.
3. Tresiba has a duration of over 40 hours and reaches steady state after 2-3 days.

Mixed Insulins (Mix)

All mixed insulins are pre-mixed combinations of intermediate-acting (NPH) and short-acting insulin analogs (Humalog 25, Humalog 50, and Novomix 30). The number indicates the percentage of short-acting insulin analog.

Guidelines for Perioperative Treatment of Diabetes

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Perioperative Plan for Dietary Regulated Diabetes Mellitus

Scedule	Intervention
Preoperatively	Fasting-P-Glucose controlled at the ward/reception Rehydrex with glucose 2,5% - 1000 ml given over 10-12 hours
Peroperatively	P-Glucose checked on request
Postoperatively	P-glucose is taken at the postop during the first hour, then as required

Perioperative Plan for Tablet Controlled Diabetes Mellitus

Scedule	Intervention
Preoperatively	Metformin is exposed 48 hours prior to surgery. Other oral antidiabetic agents (tablets) are exposed at the day of surgery. Fasting-P-Glucose controlled at the ward/reception Rehydrex with glucose 2.5% -1000 ml is given in 10-12 hours.
Peroperatively	P-Glucose checked on request Peroperative losses are replaced by non-glucose-containing solutions.
Postoperatively	P-Glucose is taken post-operatively during the first hour, then as requested

Perioperative Plan for Insulin Treated Diabetes Mellitus

Scedule	Intervention
Preoperatively	Orally taken antidiabetics (tablets) are exposed prior to surgery. Metformin is exposed 48 hours prior to surgery. Fasting-P-Glucose is controlled at the ward/reception If P-Glucose < 4 or > 12 mmol/L contact the anesthesiologist in charge In the morning 1000 ml of 5% Glucose is blended with 40 mmol Na and 20 mmol K and given in 10-12 hours (80-100 ml/h). Insulin: If the patient usually takes basic insulin (intermediately acting: Humulin NPH, Insuman Basal, Insulatard, Lantus or Levemir) in the evening, this is given in the regular dose. If the patient usually takes basic insulin in the morning, this is given in the regular dose. Short acting meal insulin in the morning (Actrapid, Humulin Regular, Apidra, Humalog or Novorapid) is not given. If the patient takes mixed insulin (Humalog Mix 25, Humalog Mix 50 or Novomix 30) in the morning, then half the dose is given, but not more than 15 Units. If over > 15 Units risk of hypoglycaemia.
Peroperatively	Continue with Glucose 5% with 40 mmol Na and 20 mmol K (80-100 ml/hour). P-glucose is checked as requested (adapted to the given type and dose of insulin). Blood and fluid losses are replaced with non-glucose-containing solutions.
Postoperatively	P-glucose is checked for the first hour after surgery and every three hours thereafter. Target: The patient should take his regular dose of meal insulin and mix insulin and eat. Basic insulin is given in the usual dose regardless of whether the patient is eating or not.

Perioperative plan for Patients with Diabetes Mellitus and Insulin Pump

Scedule	Intervention
Preoperatively	Fasting-P-Glucose is controlled at the ward/reception The insulin pump is disconnected in the morning and instead, half of the regular daily basis dose is given as long acting insulin, e.g. Lantus. For example: If the patient has 22 E/day give ½ dose like Lantus ie. 11 E In this connection, Glucose is added 5% with 40 mmol Na and 20 mmol K 1000 ml in 10-12 hours.
Peroperatively	Continue with Glucose 5% with 40 Na and 20 K (80-100 ml / h) P-glucose is checked if needed Blood and fluid loss are replaced with non-glucose-containing solutions
Postoperatively	P-glucose is postoperatively taken during the first hour and thereafter every three hours. When the patient himself can take responsibility for the maintenance of his pump, it is switched on. If this is not possible, half the base dose is given as long acting insulin in the evening. For example. Lantus.

If normalized metabolic control cannot be achieved postoperatively with the above regimen, a specialist in diabetes should be consulted. Follow-up should be done with a new measurement of HbA1c.

Diabetic Ketoacidosis (DKA)

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Diabetic ketoacidosis (DKA) is an acute complication of diabetes caused by absolute or relative insulin deficiency. Absolute insulin deficiency occurs if insulin-dependent diabetics do not receive insulin, while relative insulin deficiency occurs when there is an excess of counter-regulatory hormones such as glucagon, catecholamines, cortisol, and/or growth hormone in relation to the body’s insulin needs. Both situations can lead to DKA, which involves metabolic acidosis, dehydration, and electrolyte disturbances. DKA can occur in both Type 1 and Type 2 diabetes. Patients require prompt and consistent management, and initial ICU care may be necessary.

Pathophysiology

Insulin functions as an anabolic hormone that, among other things, facilitates glucose transport into most cells, increases glycogen formation in liver and muscle cells, inhibits gluconeogenesis, and reduces fat breakdown by inhibiting the enzyme lipase. Glucose levels are normally regulated within a narrow range, between 4-5.6 mmol/L, by the stimulation of the endocrine pancreas to increase insulin secretion at rising glucose levels. Most of the body’s cells require insulin for glucose to pass through the cell membrane in meaningful concentrations and then be used for ATP production, although nerve cells are an important exception that does not require insulin for glucose transport, which is why the brain’s metabolic needs can be met despite insulin deficiency.

In the case of absolute or relative insulin deficiency, the opposite of insulin’s effects occurs: hyperglycemia arises as glucose remains outside the cells and glycogen is broken down; protein breakdown and additional hyperglycemia occur via increased gluconeogenesis; free fatty acids accumulate through increased lipase activity, which are first converted to acetyl-Coenzyme A and then to ketone bodies (acetone, beta-hydroxybutyrate, and acetoacetate) in the liver. This process causes osmotic diuresis and vomiting, leading to dehydration and electrolyte loss, as well as the accumulation of acidic ketone bodies and poor peripheral perfusion, resulting in metabolic acidosis (see image). Without treatment with insulin, this condition in adults will lead to death through circulatory collapse and/or lethal acidosis, while cerebral edema is often the direct cause of death in pediatric populations. The pathophysiological mechanisms behind cerebral edema are not fully understood.



The biochemical criteria for the diagnosis of diabetic ketoacidosis are:

• Hyperglycemia (P-glucose >11 mmol/L)
• Venous pH < 7.3 or bicarbonate <15 mmol/L
• Ketonemia and/or ketonuria (blood ketones ≥ 3 mmol/L)

Treatment

The most important aspects of treatment are fluid replacement, insulin, and adequate potassium supplementation.

• Give 1 liter of NaCl over 30 minutes, followed by 1 liter of NaCl over 1 hour, then 1 liter over 2 hours.
• Correct and monitor hypokalemia
• Administer 20 mmol of magnesium
• When B-glucose reaches 15 mmol/L, switch to glucose with Na and K.

Fluid – Rehydration

There is no strong evidence for differences between Ringer’s acetate and sodium chloride in time to resolution of acidosis. Studies have shown that the risk of cerebral edema increases if measured p-sodium does not increase after treatment initiation, and the goal is to keep sodium within the normal reference range (upper). So-called pseudohyponatremia is common in ketoacidosis due to the dilution effects of hyperglycemia and can be corrected with the formula:

P-Na_corrected = P-Na_measured + 2.4 x [(P-glucose – 5.6)/5.6]

(Example: measured P-Sodium 129, P-Glucose 30 mmol/L: P-Na_corrected = 129 + 2.4 x [(30 – 5.6)/5.6] ≈ 139 mmol/L)

In cases of pronounced corrected hyponatremia (Na_corrected < 130), sodium chloride should be chosen, while Ringer’s acetate is suitable in other cases.

Insulin

The only treatment that can resolve diabetic ketoacidosis is insulin. Note, however, that insulin treatment must be preceded by fluid therapy! Insulin infusion can be started after an hour of rehydration and usually together with potassium, except in cases of pronounced hyperkalemia (potassium > 5.2 mmol/L). A steady infusion rate of 0.1 units/kg can be started without an insulin bolus.

Potassium

The patient is always hypokalemic, and potassium is given at P-K < 5.2 with an infusion rate of 10 – 20 mmol/hour. Due to the acidosis, apparent hyperkalemia is often seen. As a guideline, potassium concentration increases by 0.6 mmol/L for every 0.1 decrease in pH, but significant variability occurs (0.2 – 1.7 mmol/L), and it is important to remember that these patients would be hypokalemic if pH were normal. With insulin administration, potassium will shift into the cells, so it is essential to monitor potassium levels with frequent blood gas checks.

Buffering?

Buffering generally has no place in the treatment of DKA but can be considered in adult patients with pronounced acidosis with pH < 6.9 after fluid therapy has been initiated. In this case, it is particularly important to monitor potassium levels, which can drop quickly and significantly.

Note: In children, buffering is contraindicated as it has been shown to increase the risk of cerebral edema despite pronounced acidosis!

Cerebral Edema

Clinically manifest cerebral edema is a rare but serious complication of DKA in children, with a mortality rate of 20%-50%. Signs of cerebral edema usually appear 4-24 hours after the start of treatment. Risk factors include:

• < 5 years of age
• Buffering
• Low pCO2
• High urea
• Insulin bolus
• Measured P-Sodium does not increase after treatment
• Severe acidosis (pH < 7.0)

Treatment with mannitol or hypertonic saline (3% NaCl) is initiated if cerebral edema is suspected, and Muir’s criteria can serve as guidance for the decision to treat.

References

• Chua et al. J Crit Care. 2012;27:138-45
• Mahler et al. Am J Emerg Med. 2011;29:670-4
• Van Zyl et al. QJM. 2012;105:337-43
• Ma et al, Pediatr Crit Care Med. 2014 Oct;15(8)
• Tasker et al, Pediatr Diabetes. 2014 Jun;15(4):261-70.
• Glaser et al, Journ Pediatr. 2004 Aug;145(2):164-71
• Kitabchi et al. Diabetes Care. 2009;32:1335-43.
• Adrogué HJ et al, J Am Soc Nephrol 2004; 15:1667
• Glaser et. al. N Engl J Med 2001 Jan 25;344
• Glaser et. al. N Engl J Med 2001 Jan 25;344
• Viallon et al. Crit Care Med. 1999;27:2690-3
• Glaser et. al. N Engl J Med 2001 Jan 25;34

Ulcer Prophylaxis – PPI

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Severe gastrointestinal bleeding (GI bleeding) has been reported in scientific studies in 1.5-8.5% of intensive care patients and has in some studies been related to increased mortality¹. In studies in recent years, the risk of gastrointestinal bleeding appears to be lower, likely due to generally better intensive care or better ulcer prophylaxis².

Stress ulcers can occur in all critically ill patients within hours due to severe stress, serious injury, surgery, shock, or infection. The ulcerations can range from erosive gastritis to perforated ulcer, they are usually superficial, with minor capillary bleeding, but can erode into the submucosa and become deeper. Underlying vessels can be damaged, causing bleeding, or in rare cases, perforation of the mucosa. The ulcerations are likely due to an imbalance between protective mucous lining and acid production in the stomach.

The mucous lining contains glycoproteins, which provide physical protection, but also bind bicarbonate, which neutralizes acid in the stomach. In many intensive care patients, the function of the mucous layer is impaired due to reduced blood flow. Reflux of bile and uremic toxins can contribute to damaging the mucosa³.

Acid production in the stomach is increased in head-injured patients but likely not in other intensive care patients⁴. Helicobacter pylori infection may be a contributing factor to stress ulcers⁵.

Stress ulcers are most common in the fundus and corpus of the stomach, but can also occur in other parts of the gastrointestinal tract, such as the duodenum and distal esophagus⁶.

In a large prospective multicenter study, a significantly increased risk of stress ulcers was observed in patients who were ventilated for over 48 hours and/or had coagulopathy, compared to other intensive care patients⁷. There are also studies that have pointed to an increased risk in other severe conditions such as head injury, shock, sepsis, liver and kidney failure, trauma, major burns, organ transplantation, previous upper gastrointestinal bleeding, and high SOFA score^8–13.

Enteral nutrition itself has a protective effect by buffering stomach acid, increasing mucosal blood flow, and inducing the secretion of cytoprotective prostaglandins and mucus¹⁵.

However, it is uncertain whether pharmacological prophylaxis can be withheld despite ongoing enteral nutrition^16,17. One study has shown that H₂ blockers in enterally fed patients actually led to increased mortality¹⁸.

Prophylaxis

To reduce the risk of developing ulcers, pharmacological prophylaxis is commonly used in intensive care patients, either administered parenterally or orally. The three types of drugs mainly used for prophylaxis are proton pump inhibitors (PPI), histamine-2 receptor blockers, and sucralfate. Which patients should receive pharmacological prophylaxis and what effect the prophylaxis has is not fully understood. Indications for prophylaxis and drug choice vary across Sweden and internationally. There is no scientific support for routine administration of ulcer prophylaxis to all intensive care patients.

Recent studies have shown questionable efficacy of prophylaxis with PPI¹⁹ but have not demonstrated significant harm either.

Currently, pharmacological ulcer prophylaxis is recommended for patients with:

• Ventilation time over 48 hours
• Coagulopathy (platelets <50, PK/INR > 1.5 x reference value, APTT > 2 x reference value)
• Gastrointestinal bleeding within the last year
• Traumatic brain injury, traumatic spinal injury, or major burns
• Two of the following: sepsis, intensive care for more than 1 week, occult gastrointestinal bleeding > 6 days, corticosteroid therapy (>250 mg hydrocortisone/day)

For other patients, an individual assessment should be made, considering the patient’s risk factors.

The choice of prophylaxis can be based on local routines, but oral medications should be used if the patient tolerates this.

Enteral nutrition is likely protective and should be initiated early; however, there is not enough knowledge today to withhold ulcer prophylaxis if the patient belongs to a risk group despite enteral nutrition.

Ulcer prophylaxis should be evaluated and discontinued when the patient no longer belongs to a risk group or when intensive care ends.

The three types of drugs used for prophylaxis are proton pump inhibitors (PPI), histamine-2 receptor blockers, and sucralfate. It appears that PPI is more effective than H2 blockers in preventing ulcers ^20,21, but there are also studies showing the opposite²². The choice of drug often depends on local routines, but it seems that proton pump inhibitors are more frequently used (in Sweden) than other preparations. Sucralfate provides less protection against stress ulceration but possibly a lower risk of nosocomial pneumonia.

Risks

Ulcer prophylaxis leads to higher pH in the stomach, which allows bacterial overgrowth in the gastric mucosa. Through reflux, these bacteria reach the throat, where they can then be aspirated into the airways, possibly resulting in pneumonia, so-called ventilator-associated pneumonia (VAP). There may be an increased risk of VAP when treating patients with prophylaxis against stress ulcers. This risk may be greater with PPI than with sucralfate and H₂ receptor blockers²³.

There is also an increased risk of Clostridium difficile gastroenteritis due to the increased pH in the stomach²⁴.

Medications Against Stress Ulcers

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Proton Pump Inhibitors

These drugs are substituted benzimidazoles that reduce the secretion of stomach acid through a specific blockade of the proton pumps of parietal cells. Usually, omeprazole, esomeprazole, or pantoprazole is given. The drugs have similar effects. The drugs are converted to active form in the acidic environment of the parietal cells, where they inhibit the H⁺/K⁺-ATPase enzyme, i.e., the last step in stomach acid production. This provides inhibition of both basal and stimulated stomach acid secretion and is independent of stimulating systems such as acetylcholine, histamine, and gastrin²⁵. Omeprazole, like all acid-blocking drugs, can reduce the absorption of vitamin B₁₂ (cyanocobalamin) due to hypo- or achlorhydria. Another side effect can be hypomagnesemia.

Omeprazole

Proton pump inhibitor. Available as enteric capsules and enteric tablets. Omeprazole is a racemate of two enantiomers that specifically inhibits the acid pump in the parietal cell. It provides a rapid onset of effect, and the effect on acid secretion is reversible with daily administration.

Omeprazole is a weak base that is concentrated and converted to an active form in the highly acidic environment of the parietal cell’s secretory channels, where it inhibits the H⁺K⁺-ATPase enzyme – the acid pump. The effect of the last step in the acid secretion process is dose-dependent and provides very effective inhibition of both basal and stimulated acid secretion, regardless of the type of stimulation.

Trade names: Omeprazole^®, Losec^®, Omecat^®, Omestad^®, Omezomyl^®.

Standard dose: 20-40 mg p.o. x 1.

Dose for bleeding ulcers: 40 mg x 2

Note: Possible dose adjustment in severe liver failure, possible clinical interaction with clopidogrel (reduced effect), interaction with certain HIV medications, azoles.

Esomeprazole

Proton pump inhibitor, S-enantiomer of omeprazole. Available for intravenous and oral use. Metabolized completely via P450, mainly CYP2C19. Can be used during pregnancy.

Trade names: Esomeprazole^®, Nexium^®, Vimovo^®.

Standard dose: 40 mg i.v. x 1; 20-40 mg p.o. x 1 granules or enteric tablets.

Dose for bleeding ulcers: 40 mg i.v. x 2

Note: Possible dose adjustment in severe liver failure, possible clinical interaction with clopidogrel (reduced effect), interaction with certain HIV medications, azoles.

Pantoprazole

Proton pump inhibitor. Available for intravenous and oral use. Almost complete liver metabolism via P-450, mainly CYP2C19.

Trade names: Pantoprazole^®, Pantoloc^®.

Standard dose: 40 mg i.v. x1; 20-40 mg p.o. x 1 as enteric tablets
Dose for bleeding ulcers: 40 mg i.v. x 2

Note: Possible dose adjustment in severe liver failure, interaction with certain HIV medications, rifampicin, and St. John’s wort.

Histamine-2 Receptor Blockers (H2 Blockers)

H₂ receptor blockers are chemically substituted aminoalkylfurans that competitively block histamine’s effect on H2 receptors. This leads to reduced activation of parietal cells and inhibits both basal and stimulated acid secretion. However, tachyphylaxis occurs over time, with a reduced effect on stomach pH. The most common drug is ranitidine. H2 receptor blockers are primarily excreted via the kidneys, likely through active secretion.

Trade names: Ranitidine^®, Inside Brus^®, Rani-Q^®, Stomacid^®, Zantac^®, Zantac Brus^®. Standard dose: 50 mg i.v. x 3 or 150 mg p.o. x 2 as tablets or oral solution. If S-Creatinine > 200 umol/l, CRRT, IHD, a lower dose is given: 25 mg i.v. x 3 or 150 mg p.o. x 1.

Note: Risk of bradycardia with rapid infusion, possible dose adjustment in severe liver failure

Sucralfate

Sucralfate is alkaline and contains aluminum sucrose sulfate. It binds to the mucosa, providing mechanical protection and stimulating factors in the mucosa that increase its resistance to harmful agents. It is best given 30 minutes before meals.

Trade name: Andapsin^®. Available as Andapsin 1 g tablets or oral suspension 200 mg /ml.

Standard dose: 1 g (5 ml) x 4

Note: Affects the absorption of other medications in the gastrointestinal tract, risk of bezoar formation

Cook DJ, Fuller HD, Guyatt GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N Engl J Med 1994; 330:377.
Cook DJ, Griffith LE, Walter SD et al. The attributable mortality and length of intensive care unit stay of clinically important gastrointestinal bleeding in critically ill patients. Critical Care. Dec; 5(6):368-75
Krag M, Perner A, Wetterslev J et al. Prevalence and outcome of gastrointestinal bleeding and use of acid suppressants in acutely ill adult intensive care patients. Intensive Care 2015 May; 41(5):833-45.
Faisy C, Guerot E, Diehl JL, et al. Clinically significant gastrointestinal bleeding in critically ill patients with and without stress- ulcer prophylaxis. Intensive Care Med. 2003 Aug;29(8):1306-13. Epub 2003 Jun 26.
Ritchie WP Jr. Role of bile acid reflux in acute hemorrhagic gastritis. World J Surg 1981; 5:189.
Schindlbeck NE, Lippert M, Heinrich C, Müller-Lissner SA. Intragastric bile acid concentrations in critically ill, artificially ventilated patients. Am J Gastroenterol 1989; 84:624.
Thompson JC. Increased gastrin release following penetrating central nervous system injury. Surgery 1974; 75:720.
Stremple JF, Molot, MD, Judson J. Posttraumatic gastric bleeding: Prospective gastric secretion composition. Arch Surg 1972; 105(2):177-185.
Watts, CC, Clark, K. Gastric acidity in the comatose patient. J Neurosurg 1969; 30:107.
Maury, E, Tankovic, J, Ebel, A et al. An observational study of upper gastrointestinal bleeding in intensive care units: is Helicobacter pylori the culprit? Crit Care Med. 2005 Jul;33(7):1513-8.
Lev R, Molot MD, McNamara J, Stremple JF. Stress ulcers following war wounds in Vietnam: a morphologic and histochemical study. Lab Invest. 1971 Dec;25(6):491-502.
Cook DJ. Stress ulcer prophylaxis: gastrointestinal bleeding and nosocomial pneumonia. Best evidence synthesis. Scand J Gastroenterol Suppl 1995; 210:48.
Shuman RB, Schuster DP, Zuckerman GR. Prophylactic therapy for stress ulcer bleeding: a reappraisal. Ann Intern Med 1987; 106:562
Martin LF, Booth FV, Reines HD, et al. Stress ulcers and organ failure in intubated patients in surgical intensive care units. Ann Surg 1992; 215: 332.
Hatton J, Lu WY, Rhoney DH, et al. A step-wise protocol for stress ulcer prophylaxis in the neurosurgical intensive care unit. Surg Neurol 1996; 46: 493.
McBride DQ, Rodts GE. Intensive care of patients with spinal trauma. Neurosurg Clin N Am 1994; 5:755.
Krag M, Perner A, Wetterslev J,  et al. Prevalence and outcome of gastrointestinal bleeding and use of acid suppressants in acutely ill adult intensive care patients. Intensive Care 2015 May;41(5):833-45.
Ephgrave KS, Kleiman-Wexler RL, Adair CG. Enteral nutrients prevent stress ulceration and increase intragastric volume. Crit Care Med. 1990 Jun;18(6):621-4.
Guillamondegui, OD, Gunter OL, et al. Practice management guidelines for stress ulcer prophylaxis, Eastern Association for the Surgery of Trauma (EAST) (Published 2008).
Pingleton SK, Hadzima SK. Enteral alimentation and gastrointestinal bleeding in mechanically ventilated patients. Crit Care Med 1983 Jan;11(1):13-6.
Raff T, Germann G, Hartmann B. The value of early enteral nutrition in the prophylaxis of stress ulceration in the severely burned patient. Burns 1997; 23:313.
Marik PE, Vasu T, Hirani A, Pachinburavan M. Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis. Crit Care Med 2010; 38:222?
Alhazzani W, Guyatt G, Alshahrani M, et al. Withholding Pantoprazole for Stress Ulcer Prophylaxis in Critically Ill Patients: A Pilot Randomized Clinical Trial and Meta-Analysis. Crit Care Med. 2017 Jul;45(7):1121-1129.
Selvanderan SP, Summers MJ, Finnis ME, et al. Pantoprazole or Placebo for Stress Ulcer Prophylaxis (POP-UP): Randomized Double-Blind Exploratory Study. Crit Care Med. 2016 Oct;44(10):1842-50.
Barkun AN, Bardou M, Pham CQ, Martel M. H2 blockers versus PPI (Proton pump inhibitors vs. histamine 2 receptor antagonists) for stress-related mucosal bleeding prophylaxis in critically ill patients: a meta-analysis. Am J Gastroenterol. 2012 Apr;107(4):507-20.
Alshamsi F, Belley-Cote E, Cook D, et al. Efficacy and safety of proton pump inhibitors for stress ulcer prophylaxis in critically ill patients: a systematic review and meta-analysis of randomized trials. Crit Care 2016; 20:120.
MacLaren R, Reynolds PM, Allen RR. Histamine-2 receptor antagonists vs proton pump inhibitors on gastrointestinal tract hemorrhage and infectious complications in the intensive care unit. JAMA Intern Med 2014; 174:564
Canadian Critical Care Trials Group. Cook D, Guyatt G, Marshall J, et al. A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. N Engl J Med. 1998 Mar 19;338(12):791-7.
Rang & Dale’s Pharmacology – 8th Edition – Elsevier (??)
McRorie JW, Kirby JA, Miner PB. Histamine2-receptor antagonists: Rapid development of tachyphylaxis with repeat dosing. World J Gastrointest Pharmacol Ther. 2014 May 6;5(2):57-62.

Hyperkalemia

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Hyperkalemia typically occurs with cell breakdown, metabolic acidosis, acute or chronic kidney failure, critical ischemia, Addison’s disease, or after the intake of potassium or potassium-sparing diuretics. Dehydration and starvation are other conditions that can lead to severe hyperkalemia. With pronounced hyperkalemia, there is a risk of severe cardiac arrhythmias, ventricular fibrillation, and circulatory collapse. Investigation and treatment must address the underlying cause, but with S-Potassium values over 6.0 mmol/L, treatment should be initiated immediately. Below are suggestions for various forms of treatment. When inducing anesthesia in a patient with hyperkalemia, the surgery should be postponed, and hyperkalemia should be corrected preoperatively at values over 5.5 mmol/L, if possible.

Treatment of Hyperkalemia

• Calcium: With QRS involvement and S-Potassium > 6.0 mmol/L: 10 ml Calcium-Sandoz 9 mg/ml over 1 minute – repeat until ECG normalizes.
• Intravenous fluid: Dilute plasma volume with NaCl 9 mg/ml 1000-2000 ml.
• Glucose-insulin drip: 20 E Actrapid/Novorapid in 500 ml 10% Glucose, give 250 ml over 15 minutes. The remainder over 2-3 hours. Monitor P-glucose and blood gases. Effect typically seen after about 15 minutes, often later.
• Sodium bicarbonate in acidosis: 100 ml IV – gives immediate effect, can be repeated. Lowers potassium by approximately 0.5 mmol/L.
• Bricanyl (terbutaline – beta2-agonist): 0.5-1 mg IV over 15 minutes. 1 mg mixed in 100 ml NaCl, administered over 30-60 minutes, monitor pulse.
• Resonium: Sodium polystyrene sulfonate, cation exchanger. 15 g x 3-4. Effect after 1-2 hours, administered rectally or orally.
• Sodium zirconium cyclosilicate (Lokelma) 10 g x 3
• Magnesium: 20 mmol IV (use caution with low blood pressure) over 20 minutes.
• Diuretics
• Possibly hemodialysis
•  
• 

Hypokalemia

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Definition of hypokalemia: S-Potassium < 3.5 mmol/L.

Symptoms and Findings

Rarely symptomatic until S-Potassium drops below 3.0 mmol/L (related to the increased gradient of membrane potential, i.e., in all muscles)

Symptoms of Hypokalemia

Muscle weakness, reduced tendon reflexes, ileus/subileus, ECG changes (depressed ST-segment, flattened T-wave, and the presence of U-wave), and increased fatigue. Cases with neuromuscular disease, critically ill patients, decreased GFR, and reduced kidney concentration ability with polyuria may be particularly sensitive to hypokalemia.

Causes of Hypokalemia

Renal loss		Non-Renal Causes
With Hypertension		With normal blood pressure
Cushing syndrom	Renal tubular acidosis	Alkalosis	Intestinal losses
Congenital adrenal hyperplasia	Fanconi syndrome	Leucemia	Diarrhéa
Primary hyperaldosteronism	Bartter's syndrom	Familiar hypokalemic periodic paralysis	Laxatives
Increased amount of renin	Diabetic keto acidosis	Sweating	Enema
Renovascular disease	Antibiotics		Anorexia nervosa
	Diuretics		Enterocutanous fistula
			Alcoholism
	Urinary K > 20 mmol /L		Urinary K < 20 mmol /L

Diagnosis and Investigation

Depending on the clinical picture and underlying cause:

• Blood tests: Hgb, Na, K, Cl, creatinine, urea, glucose, acid-base status, CK, renin, cortisol, possibly 17α-OH-progesterone, 11-deoxycortisol, and aldosterone
• Urine: Urine dipstick (glucose, protein), Na, K, Cl, osmolality.
• Other: Standard ECG and ECG monitoring with telemetry.

Treatment and Follow-up

Potassium supplementation should primarily be administered orally, but in intensive care settings, potassium is preferably given parenterally with caution. The concentration in intravenous solutions should be up to 40 mmol KCl per 1000 ml solution, typically 20-40 mmol/L. If higher concentrations are desired, the infusion must be labeled and administered via a central venous catheter (CVC). This is to avoid dangerous and rapid infusion of potassium. If necessary, the rate of administration can be increased, but the maximum rate is 0.5 mmol/kg/hour (maximum 20 mmol/hour for an adult patient). In such cases, the infusion must, for safety reasons, be administered through a separate needle/lumen where no other infusion or medications are administered. At high infusion rates, S-Potassium must be monitored with frequent blood tests. Strong potassium solutions are highly irritating to veins, skin, and subcutis, and should be administered via central catheters. Extremities where potassium infusions are administered should not be covered during surgery so that the access site is not concealed during ongoing anesthesia.

Hyponatremia

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Hyponatremia (S-Na <135 mmol/L) is the most common electrolyte disturbance, affecting 15-30% of hospitalized patients. It leads to increased mortality, morbidity, and prolonged hospital stays. Hyponatremia is not primarily a pure sodium deficiency but a relative water excess. When hyponatremia occurs acutely, there is a risk of brain edema as fluid shifts intracellularly when blood osmolality decreases. The brain needs about 48 hours to adapt to the hypotonic environment. Once this has occurred, the risk of brain edema is reduced, but the risk of osmotic demyelination syndrome increases if serum sodium levels rise too quickly. This is because the myelin sheaths that insulate neurons can be damaged during a rapid shift in osmolality. This is the rationale behind the importance of distinguishing acute from chronic hyponatremia before initiating correction.

Common causes of hyponatremia include SIADH, diuretics, ethanol, hyperglycemia, polydipsia, renal failure, medications, hypotonic fluid administration, and to some extent, physical exercise with excessive water intake.

Wide variation, from mild, nonspecific symptoms to very severe life-threatening symptoms with brain edema and herniation. Acutely occurring hyponatremia usually presents with more pronounced symptoms, while hyponatremia developing over time may be asymptomatic despite very low serum sodium levels.
Common symptoms include balance difficulties, cognitive impairment, headache, nausea, vomiting, seizures, altered consciousness, and confusion.

Investigation

Differentiating between acute hyponatremia (documented duration < 48 hours). If the duration is unclear, assume the hyponatremia is chronic unless the history clearly suggests otherwise, such as in long-distance running.

Exclude hyperglycemia as a cause of hyponatremia, as well as other iso/hyperosmolar conditions such as the administration of mannitol, contrast agents, urea, and various alcohols. These conditions have normal or high serum osmolality, and the hyponatremia is secondary.

Testing for Hyponatremia

S-Na, S-K, U-Na, U-K, S-Osm, U-Osm, P-glucose, S-creatinine, liver function tests, TSH, free T4, S-cortisol.

Assess the patient’s volume status according to the diagram below (hypo-, hyper-, or euvolemic?). The diagram also indicates common underlying causes of the different conditions.



Investigation of Hyponatremia

Treatment of Hyponatremia

• Treat the underlying condition.
• Discontinue medications that may have triggered hyponatremia.
• In cases of strong clinical suspicion of acute adrenal insufficiency, Addison’s disease, treatment with hydrocortisone (Solu-Cortef) and 0.9% NaCl IV should be initiated.
• Check other electrolytes and correct if necessary.
• Correct hyponatremia cautiously.

Chronic hyponatremia (>48 hours) with mild symptoms should first be investigated, and underlying causes treated. Hyponatremia should be corrected slowly, with a goal to raise sodium by a maximum of 0.5 mmol/L/hour, totaling <8 mmol/L/day. In awake, normovolemic patients, this can be done through fluid restriction. Hypovolemia is treated with 0.9% NaCl, and hypervolemia with loop diuretics. Calculating the infusion rate of 0.9% NaCl is challenging as the formulas do not account for how much sodium is lost through urine, etc. The calculation should, therefore, be seen as a guideline that is adjusted based on testing depending on how the patient responds to the treatment.

For chronic hypovolemic hyponatremia where slow correction is planned, an initial infusion rate can be calculated as follows:

• Target S-Na 130 mmol/L
• Measure current S-Na (mmol/L) and weight V(kg)
• Calculate body water volume KV (L), women: Weight x 0.5, men: Weight x 0.6
• Determine the net increase in S-Na (mmol/L); 130 minus current value;
  • If the planned net increase is >8 mmol/L: Calculate the total time (hours) to reach the goal with 0.3 mmol/L/hour.
  • If the planned net increase is <8 mmol/L: Calculate the total time (hours) to reach the goal with 0.5 mmol/L/hour.
• Calculate total Na requirement (number of mmol); KV(L) x net increase in S-Na
• Calculate the fluid volume (L) needed; total Na requirement (mmol)/Na concentration (mmol/L) in the infusion solution
• Calculate the infusion rate (ml/hour); planned fluid volume (ml)/planned number of hours

Severe symptomatic hyponatremia, such as seizures, must be corrected quickly initially until the severe symptoms subside. Raise S-Sodium initially by 1-2 mmol/L/hour using 0.9% or 3% NaCl IV. When symptoms subside, reduce the correction rate, and the total daily correction should not exceed 8 mmol/L/day.

If rapid correction is necessary, 3% NaCl 1 ml/kg increases S-Na by about 1 mmol/L.
Hypertonic 3% NaCl is obtained by adding 160 mmol Na (40 ml Addex Na) to 500 ml 0.9% NaCl. Frequent testing is required if hypertonic saline is given due to the risk of overcorrection.

It is crucial to closely monitor during correction! Initially every hour, which can be spaced out as the patient stabilizes and the increase occurs at the planned rate. Increased diuresis may indicate reduced ADH release and be a sign of too rapid correction. Reduce the infusion rate and check S-Na.

Too rapid correction?
– Slow down the infusion rate or stop
– Administer sodium-free fluid (glucose, water orally/through a tube)
– In cases of large diuresis, consider desmopressin (Minirin). NOTE! Be aware of the risk of brain edema!
– Reversing, i.e., dilution if sodium rises too quickly.

References

• Chantzichristos et al, Vårdprogram för hyponatremi, 2012.
• Spasovski et al, Clinical Practice Guideline on Diagnosis and Treatment of Hyponatremia. Eur J Endocrinol. 2014 Feb 25;170(3):G1-47
• Verbalis et al, Diagnosis, Evaluation, and treatment of Hyponatremia: Expert panel recommendations. Am Journal of Med 126:S5-S42

Hypophosphatemia

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Phosphorus is stored in large amounts in the body – it is the second most abundant mineral. About 80% is stored in the skeleton and teeth, 20% in the blood and various body tissues. There are approximately 12 g of phosphorus per kilogram of fat-free tissue. About 85% of phosphorus exists as inorganic calcium phosphate in a 2:1 ratio compared to phosphorus in bone tissue and teeth. Blood plasma contains 3.5 mg of phosphorus per 100 ml, which is about half the amount of calcium present. There are 30–45 mg of phosphorus per 100 ml of whole blood and 3.5 mg per 100 ml of blood plasma. Levels are maintained through reabsorption in the kidneys, and this level is related to the concentrations of calcium and phosphorus in blood plasma, PTH, and vitamin D3.

Phosphorus is a very important substance for the skeleton and is a part of the structure of cells, even in soft tissues. Phosphorus is also a component of nucleic acids, which form the genetic code in all cells and are therefore important for growth, repair, and maintenance of all body tissues, as well as for protein synthesis. Phosphorus helps calcium attach to the protein matrix in the skeleton. Phosphorus is also a component of ATP (adenosine triphosphate), ADP (adenosine diphosphate), and AMP (adenosine monophosphate). It is necessary for energy production and transport and plays an important role in the phosphorylation of monosaccharides for energy. Phosphorus enables nutrients to pass through cell membranes or to be transported in the blood.

Symptoms of phosphorus deficiency in the central nervous system may include fatigue, paresthesias, tremor, seizures, muscle weakness, respiratory failure, and paresis. Other symptoms of phosphorus deficiency are vomiting, poor appetite, bone pain, depression, and osteomalacia.

Serum contains different forms of phosphate, but only inorganic phosphate is measured in the blood, and this serves as the transport form of phosphorus and also acts as a pH buffer.

Hyperphosphatemia is caused by decreased phosphate excretion, as seen in renal insufficiency, or increased tubular phosphate reabsorption, as in hypoparathyroidism.

Hypophosphatemia can be caused by

• Malnutrition, starvation
• Shift of phosphate from the extracellular to the intracellular space (e.g., during treatment of malnutrition)
• CRRT treatment
• Renal losses, e.g., due to tubular defects (familial hypophosphatemia)
• Decreased intestinal absorption

The kidneys’ normal response to phosphate depletion is to increase phosphate reabsorption, which means that phosphate excretion in the urine can be practically zero. Most of the filtered phosphate is reabsorbed in the proximal tubule via the sodium-phosphate cotransporter.

Reference Range for Normal Values

Men > 50 years	0.75 – 1.4 mmol/L
Men 18 – 50 years	0.7 – 1.6 mmol/L
Women > 18 years	0.8 – 1.5 mmol/L

Symptoms of Hypophosphatemia

• Fatigue
• Paresthesias
• Tremor
• Muscle weakness
• Rhabdomyolysis
• Seizures
• Coma

Overt symptoms of hypophosphatemia rarely appear unless phosphate levels are below 0.64 mmol/L.

Severe symptoms such as muscle weakness and rhabdomyolysis are usually not seen until phosphate levels are below 0.32 mmol/L. There is some evidence that even mild hypophosphatemia may be associated with poorer clinical outcomes. Most patients with hypophosphatemia do not need any treatment other than that given for the underlying cause. For example, hypophosphatemia associated with correction of diabetic ketoacidosis will spontaneously resolve with normal food intake.

Intravenous phosphate is potentially dangerous as it can precipitate with calcium and cause side effects such as:

• Hypocalcemia (due to precipitation with calcium)
• Renal failure (due to precipitation with calcium in the kidneys)
• Severe arrhythmias

Treatment of Hypophosphatemia

Oral phosphate is recommended for patients with S-phosphate levels between 0.32 and 0.63 mmol/L. Administer 30-80 mmol/day divided into 3-4 doses. Check S-phosphate 2-12 hours after the last dose.

If intravenous treatment is necessary due to severe hypophosphatemia (S-phosphate < 0.32 mmol/L) or if oral treatment is not possible, the following regimen is recommended:

• For S-phosphate < 0.40 mmol/L, administer 0.5 mmol/kg (maximum 80 mmol) over 8-12 hours
• For S-phosphate > 0.40 mmol/L, administer 0.2 mmol/kg (maximum 30 mmol) over 6 hours
• Phosphate should be administered slowly. Maximum 100 mmol over at least 8 hours.

Higher doses are described but should not be given in cases of concurrent renal failure.

S-phosphate levels should be monitored every 6 hours during intravenous phosphate administration, and the patient should, if possible, be switched to oral phosphate when S-phosphate exceeds 0.48 mmol/L.

Dilution and Preparation for Infusion

Glycophos infusion concentrate 1 mmol/ml. A 20 ml vial contains 20 mmol phosphate and 40 mmol sodium.  Maximum 100 mmol glycophos should be added alone per 1000 ml glucose (5%, 10%, or 20%).

The daily normal phosphate requirement for adults receiving intravenous nutrition is typically 10-30 mmol. This means that 20 mmol Glycophos can be added to 250 mmol glucose 5% (nothing else added to the same bag). The infusion is administered over at least 8 hours.

Refeeding Syndrome

Refeeding syndrome is a condition that can occur due to fluid and electrolyte shifts during nutritional rehabilitation (whether oral, enteral, or parenteral) of malnourished patients. The syndrome typically occurs after rapid and abundant nutrition in cases of malnutrition , such as in the treatment of severe anorexia or other starvation conditions.

A so-called “refeeding syndrome” is characterized by:

• Hypophosphatemia (the hallmark and dominant cause of the syndrome)
• Hypokalemia
• Heart failure
• Peripheral edema
• Rhabdomyolysis
• Seizures
• Hemolysis
• Respiratory failure

The cause is that phosphate stores are depleted during starvation, and when the patient is then provided with carbohydrates, insulin is released, leading to phosphate uptake into cells (along with potassium and magnesium), which reduces serum phosphate levels. Insulin also causes cells to start producing molecules that require phosphate, such as ATP; this further depletes the body’s phosphate stores. The lack of phosphorylated intermediates that occurs causes tissue hypoxia, myocardial dysfunction (reduced contractility, arrhythmias), respiratory failure due to diaphragm contraction impairment, hemolysis, rhabdomyolysis, and seizures. If “refeeding” occurs, nutritional intake should be reduced, and aggressive correction of hypophosphatemia, hypokalemia, and hypomagnesemia should be undertaken. The syndrome can be prevented by slowly refeeding over the first 1–2 weeks in cases of malnutrition or starvation and closely monitoring electrolytes and phosphate levels.

Malignant Hyperthermia

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Guidelines for Treatment of an Acute Reaction Similar to Malignant Hyperthermia

Malignant hyperthermia (MH) sensitivity is an inherited condition where potent inhalation anesthetics and/or succinylcholine can trigger a life-threatening reaction during anesthesia. Signs of hypermetabolism and muscle involvement are observed during an MH reaction. MH reactions are rare and important to identify, as they are potentially life-threatening but treatable. A previous complication-free anesthesia with MH-triggering agents does not exclude MH sensitivity.

Triggering agents: Succinylcholine + inhalation gases.

Symptoms: Muscle rigidity, rapid temperature increase (1°C/5 min), elevated EtCO2, sweating, tachycardia.

Treatment: Hyperventilate with 100% O2 at 2-3 times the minute ventilation, switch to TIVA, disconnect the vaporizer, and end the operation.

Dantrolene starting dose: 2.5 mg/kg (via large-bore IV/CVC) – repeat 1 mg/kg until the temperature decreases.

Agents that Can Trigger an MH Reaction

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1. Potent Inhalation Anesthetics
• Sevoflurane (Sevorane^®)
• Desflurane (Suprane^®)
• Older inhalation anesthetics: Isoflurane (Forene^®), Halothane^®, Enflurane, Ether, etc.
2. Depolarizing Muscle Relaxants
• Succinylcholine (Celokurin^®)

Signs of an MH Reaction

The clinical signs of an MH reaction can vary widely, from few to many. The course of the reaction can be anything from explosive to more subtle. Therefore, the clinical diagnosis can be difficult to make. An MH reaction almost always develops during anesthesia or, in rare cases, immediately postoperatively. No symptom is pathognomonic for an MH reaction, making the diagnosis of an MH reaction one of exclusion.

Early Signs from Various Organ Systems:

Metabolism

Increased metabolism – hypermetabolism (“metabolic storm”)

• Signs of increased CO₂ production (EtCO₂, or pCO₂), tachypnea. The CO₂ value must be related to the minute volume. If capnography is unavailable, a high respiratory rate and rapidly exhausted and hot CO₂ absorber suggest increased CO₂ production.
• Increased O₂ consumption
• Metabolic and respiratory acidosis
• Profuse sweating
• Mottled skin

Musculature

• Masseter spasm after administration of succinylcholine (Celokurin®). Masseter spasm = “jaws of steel” lasting for two minutes or more.
• Generalized muscle rigidity. Generalized muscle rigidity usually occurs later in the course.

Cardiovascular

• Unexplained tachycardia
• Arrhythmias (especially ectopic ventricular beats, VES in bigeminy)
• Unstable blood pressure

Late Signs

• Rapid temperature increase (core temperature). Measure temperature centrally: rectally, in the bladder, esophagus, or CVC. The temperature increase is secondary to hypermetabolism, so elevated temperature is not an early sign.
• Hyperkalemia. Sudden hyperkalemia after administration of succinylcholine also raises suspicion of muscular dystrophy, such as Duchenne’s muscular dystrophy.
• Significant elevation of CK (creatine kinase)
• Significant elevation of myoglobin (plasma/urine)
• Dark-colored urine (Coca-Cola/port wine-colored) (sign of myoglobinuria)
• Renal failure
• Severe arrhythmias or cardiac arrest
• Disseminated intravascular coagulation
• Multiple organ failure
• Brain death/death

Differential Diagnoses

• Shallow anesthesia
• Infection/sepsis
• Insufficient ventilation or inadequate fresh gas flow
• Faulty anesthesia machine
• Iatrogenic temperature increase
• Another neuromuscular disease
• Anaphylactic reaction, pheochromocytoma, thyrotoxic crisis, reaction triggered by ecstasy or other stimulants, malignant neuroleptic syndrome (NMS).

Treatment

Treatment should be initiated immediately. Dantrolene is the highest priority. Delaying dantrolene administration increases mortality and morbidity. Symptoms can vary significantly, and treatment should be adjusted accordingly.

Immediate

• Stop the administration of all triggering agents. Remove the vaporizer. If this is not possible, turn it off.
• Increase to 100% oxygen and increase fresh gas flow to > 10
  
  liters/min.
• Hyperventilate 2-3 times normal minute volume with 100% oxygen.
• Inform everyone in the room and call for help. Request dantrolene. A lot of staff will be needed to mix dantrolene, take samples, arrange access, etc.
• Switch to total intravenous anesthesia. Do not waste time changing tubes or the anesthesia machine; this can be done later. Dantrolene is the highest priority.
• Decide whether the surgical procedure should/can be terminated or not.
• If the operator is inexperienced, call in an experienced colleague.

Dantrolene (Dantrium^®)

• Administer dantrolene 2 mg/kg intravenously. Vials of 20 mg are mixed with 60 ml sterile water. It is easiest to use room-temperature sterile water.
• Repeat the administration until symptoms subside.
• If there is a shortage of dantrolene, request more from another medical facility.
• The maximum dose of dantrolene is 10 mg/kg, but this dose may need to be exceeded in rare cases.

Monitoring

• Continue with the initiated monitoring (SaO₂, EtCO₂, EKG, Blood Pressure).
• Measure temperature centrally (rectally, bladder, esophagus, or CVC). Peripheral temperature measurement is unreliable in this situation.
• Ensure there are good, well-functioning venous access points.
• A urinary catheter, arterial line, and CVC may be needed. Administering dantrolene takes priority over CVC and arterial line initially.
• Lab tests
• Blood gas
• Electrolyte status
• CK
• Myoglobin
• Blood sugar
• Creatinine
• Liver function tests
• Coagulation status
• Additional tests as indicated
• Monitor/care for the patient in an intensive care or postoperative unit for at least 24 hours after an MH reaction. Symptoms may recur and require treatment.
• Compartment syndrome may develop. Monitor as needed.

Symptomatic Treatment

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Treat Hyperthermia

High priority.

• Administer 2-3 liters of cold NaCl, Ringer’s acetate, or similar solution.
• Surface cooling: wet sheets or ice in the axillae and groin.
• Other methods, such as devices for surface or intravenous cooling.
• Stop cooling the patient when the core body temperature drops to ~38-38.5°C. The temperature will continue to drop after cooling stops. There is a risk of rebound phenomena with excessive cooling.

Treat Hyperkalemia

High priority.

• In life-threatening hyperkalemia, administer calcium, such as calcium gluconate 10-20 ml to adults.
• Glucose and insulin intravenously as needed, e.g., 20 units of “rapid insulin” in 1000 ml of 5% glucose at 100-200 ml per hour. More insulin may be needed. Monitor for hypoglycemia.
• Dialysis may be necessary.

Treat Acidosis

• Hyperventilate to normocapnia if possible.
• Administer Tribonate^® or sodium bicarbonate if pH < 7.2.

Note that the administration of sodium bicarbonate increases CO₂ load.

Treat Arrhythmias

• Amiodarone (Cordarone^®) 300 mg for adults (3 mg/kg)
• β-blockers for persistent tachycardia
• Do not administer calcium channel blockers.

Maintain Good Diuresis > 2 ml/kg/hr with

• Diuretics such as furosemide or mannitol. Note that each vial of dantrolene contains 3 g of mannitol.
• Fluids such as Ringer’s acetate or NaCl.

Patients who have experienced a suspected MH reaction should undergo an MH investigation with an IVCT test and mutation analysis. IVCT = in vitro contracture test. This test involves extracting a small muscle sample and exposing it to halothane or caffeine, and then stimulating it electrically. A negative mutation test alone does not rule out MH sensitivity. The patient’s close relatives should be informed.

References

• Glahn KP et al. Recognizing and managing a malignant hyperthermia crisis: guidelines from the European Malignant Hyperthermia Group. Br J Anaesth. 2010 Oct;105(4):417-20.
• Rosenberg H, et al. Malignant hyperthermia: a review. Orphanet J Rare Dis. 2015;10:93.
• Hopkins PM, et al. European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility. Br J Anaesth. 2015 Oct;115(4):531-9.
• Hyperkalemia http://www.internetmedicin.se/page.aspx?id=899 (accessed 2017-02-26)

There is an app for iPhone that may be helpful:

Appstore: MHapp – Malignant Hyperthermia

Steroid Equivalencies

100 mg Hydrocortisone (Solu-Cortef) ≈ 25 mg Prednisolone ≈ 3.3 mg Betamethasone (Betapred) ≈ 20 mg Methylprednisolone (Solu-Medrol)

• Hydrocortisone (Solu-Cortef)
  • Dosage: 50-100 mg intravenously. Then 50-100 mg 2-3 times daily.
• Betamethasone (Betapred)
  • Water-soluble glucocorticoid. Dosage: 4 mg preoperatively for emergency surgeries, then 2 mg 4 times on the day of surgery and the first postoperative day.
• Methylprednisolone (Solu-Medrol)
  • Dosage: in shock, administer 30 mg/kg slowly intravenously. Often 500-1000 mg is given intravenously as a bolus. For cerebral edema treatment, administer 40 mg 4 times daily.