Intensive Care – Neuro Intensive Care

Posted by Fredrik Bergman, Senior Physician in Anesthesia & Intensive Care. Sahlgrenska University Hospital.
Updated 2019-06-13


Acute liver failure (ALF) is defined as progressive liver disease with encephalopathy and PK/INR > 1.5 in a patient without prior known liver disease.

The condition is characterized by rapid deterioration in the synthesis capacity of the liver which causes coagulopathy and encephalopathy that occur within days to weeks. ALF is often preceded by nausea and vomiting. The condition is often complicated by multiple organ failure (MOF) with vasoplegic cardiovascular failure, renal failure and brain edema, as liver necrosis triggers inflammatory cascades. Resuscitation with fluids (crystalloids, albumin), vasopressor drugs (norepinephrine) and adequate oxygenation (O2, ventilator) prevents further ischemic organ damage and stimulates hepatocyte regeneration. There is a high risk of hypoglycaemia and B-glucose must be closely monitored and corrected. Patients with acute liver failure may initially be unaffected, but can very rapidly deteriorate with the development of multiple organ failure.

Correct classification of ALF is important because the time frame for symptom development affects the prognosis. One can use O’Grady’s classification as follows:

A.    Hyperacute Hepatic Failure. Encephalopathy develops within 7 days from the debut of icterus. The condition entails the greatest risk of brain edema.

B.    Acute Hepatic Failure – development of encephalopathy from 8 to 28 days after icterus. Fairly high risk of brain edema.

C.   Subacute Hepatic Failure – development of encephalopathy 28 days to 12 weeks after icterus. Low risk of brain edema. The incidence of brain edema is highest in the hyperacute group and the prognosis without liver transplantation is worst in the subacute group. When ALF is due to toxins such as overdose of paracetamol, poisoning with amanita phalloides (white fly fungus) or ischemia, encephalopathy may occur before evident clinical symptoms and nausea. ALF is a condition where the severity depends on how many hepatocytes are destroyed.

Causes of Acute Liver Failure

The reason for ALF varies between different parts of the world. In developing countries, viral hepatitis predominates. In Europe and the United States, drug-induced liver damage is the most common. In Europe, etiology varies to ALF, in Spain, viral hepatitis is the most common cause of ALF whereas in Scandinavia and Britain, drug-mediated ALF (paracetamol/acetaminophen) dominates. In 11% of patients in Sweden, the cause of liver failure is not found (17% in UK). These are called cryptic liver failure everything. NANB Hepatitis (non-A non-B Hepatitis). In Sweden, 42% of ALF is due to paracetamol, 15% of other drugs, 3% of HAV, 4% of HBV and 25% of other causes, e.g. ischemic hepatitis, autoimmune hepatitis, Budd Chiaris syndrome, any malignancy, fungal poisoning, Wilson’s disease, pregnancy-impaired liver failure (1-3% HELLP – Hemolysis Elevated Liver Enzymes and Low Plateletes), AFLP. Causes of ALF can coincide with causes of ACLF (acute upon chronic liver failure)

Viral Hepatitis

  • Hepatitis A, B, C, D and E
  • Herpes Simplex 1 and 2
  • Human Herpes virus 6 (HHV-6)
  • Epstein-Barr virus (EBV)
  • Cytomegalovirus (CMV)
  • Varicella Zoster virus (VZV)
  • Parvovirus B19
  • Adenovirus (children)

Drugs and drugs that can cause ALF

  • Acetaminophen/Paracetamol
  • Other drugs; (idiosyncrasies or direct toxic damage), eg NSAIDs, tricyclic antidepressants
  • (TCAs), SSRIs, neuroleptics, valproate, carbamazepine, phenytoin, disulfiram, tuberculosis, fungicides, amiodarone, lisinopril, verapamil, sulfasalazine,
  • Inhalation anesthetics such as sevoflurane, desfluran
  • Illegal drugs – such as cocaine, ecstasy and others
  • Internet drugs – new psychoactive substances with unclear effects are constantly on the market
  • Alcohol – in the context of ACLF.

Toxins

  • Mushroom poisoning – White mushroom and Death Cap (Amanita virosa, Amanita phalloides). Amatoxin and phallotoxin.
  • Some herbal remedies
  • Organic solvents – carbon tetrachloride, perchlorethylene, acetone, etc.
  • Iron elements – phosphorus, copper, lead, iron
  • Insecticides

Immunological causes

  • Autoimmune hepatitis: ANA, SMA, AMA
  • Heat stroke: often in combination with any drug that causes overactivity and or disturbed thermoregulation
  • GVH after transplantation of bone marrow or intestines

Bacterial Infections

  • Sepsis
  • Food poisoning (Bacillus Cereus et al)
  • Liver disease – Sepsis, tropical diseases, etc.
  • Miliar TBC

Metabolic state

  • Wilson’s disease (Copper storage in the liver)
  • Hemochromatosis
  • Pregnancy-induced liver failure
  • AFLP (acute fatty liver of pregnancy)
  • HELLP (hemolysis elevated liver enzymes and low plateletes) in preeclampsi.
  • Reyes syndrome – affects children after viral infection

Cardiovascular Conditions

  • Arterial ischemia/anoxia – low or temporarily eliminated perfusion in pronounced left ventricular failure, circulatory arrest, severe bleeding, etc.
  • Venous stasis – liver venous thrombosis, right ventricular failure, pulmonary embolism etc.
  • Thrombosis – hepatic artery thrombosis
  • Intravenous leiomyomatosis

Malignant infiltration in the liver

  • Hepatocellular cancer (HCC)
  • Cholangiocarcinom
  • Lymphoma
  • Non-Hodgkin’s lymphoma
  • Hodgkin’s disease
  • Leukemia
  • Malignant melanoma
  • Malignant histiocytosis
  • Metastasis

Symptoms and Clinical findings in Acute Liver Failure

The clinical picture of acute liver failure varies depending on how fast the condition develops (compare hyperacute, acute and subacute hepatic failure). Irrespective of the initial cause, ALF causes symptoms that differ from the symptoms that develop in chronic liver disease (see later ACLF).

Often, non-specific symptoms develop such as fatigue and nausea in a previously healthy individual. Thereafter, there is a sore throat and drowsiness, which can quickly progress to coma, sepsis and multi-organ failure (MODS). The progressive liver damage causes the primary symptoms and leads to multiple complications in multiple organs and organ systems (activation of both pro and antiinflammatory cytokines, SIRS).

Child Pugh Score for Cirrhosis Mortality

Score123
EncephalopathyNo EncephalopathyGrade 1-2Grade 3-4
AscitesAbsentSlightModerate
INR<1.71.7-2.2>2.2
Albumin>3.5 g/dL (>35 g/L)2.8-3.5 g/dL (28-35 g/L)<2.8 g/dL (<28 g/L)
Bilirubin (Total)<2 mg/dL (<34.2 µmol/L)2-3 mg/dL (34.2-51.3 µmol/L)>3 mg/dL (>51.3 µmol/L)
Total Score:5-6 points7-9 points10-15 points
Category:Child Class AChild Class BChild Class C
Five year survival:80 percent50 percent35 percent
Life Expectancy:15-20 yearsIndication for transplant evaluation1-3 years
Abdominal surgery peri-operative mortality:10 percent30 percent82 percent
Child Pugh Score for Cirrhosis Mortality

Differential Diagnoses

  • Sepsis with MODS
  • Overdose of drugs (medications)
  • Circulatory failure with secondary severe liver effect
  • Brain edema in herpes encephalitis with concomitant liver effect (compare primary herpes hepatitis)

Medical Examination and Blood Sampling

  • Examination must be done continuously as the patient’s condition can be rapidly deteriorated.
  • Diagnosis of ALF – probable etiology by name and other available data (possibly liver biopsy).

Note: As early as possible, do not miss the “window” before any encephalopathy obstructs or eliminates evaluation of autoimmune disease. History from family members. Earlier diseases such as autoimmune disease, thromboembolism, psychiatric disease, cardiovascular disease, malignancy, pain syndrome, impaired immune system, etc.

Furthermore, routinely validate:

  • Prognosis and possible liver transplantation assessment
  • Hemodynamic monitoring for early detection of complications (ICU patient)

Note any Contributing Underlying Condition

  • One goal is to detect treatable etiology for ALF to increase survival among non-transplantation candidates and those who could receive a transplant but have not yet been operated
  • The appearance of the symptoms in a time perspective (in order to determine whether the liver failure is hyperacute, acute or subacute). Time of first symptoms (which may be unspecific as fatigue and nausea). Time of icterus and changed mental status.
  • Summary of all drug exposure in the last 3-6 months. Please note overconsumption of paracetamol (modified release preparation?). Of particular interest are antiepileptics, antibiotics, NSAIDs. Please note possible occasions of acute or subacute intoxication.
  • Herbal remedies
  • Drug use, especially intravenous addiction, but not only.
  • Alcohol consumption
  • Travel abroad: Endemic areas for viral hepatitis.
  • Risk factors for Hepatitis A and E. Whether the patient has eaten or consumed drinking water that may have been contaminated, cohabiting with infected family members or having sexual partners with possible infection.
  • Risk factors for Hepatitis B, C, D and HIV: intravenous drug addiction, drug accessories, risky sexual activities, any tattoos (eg, if performed in countries where you do not routinely sterilize the needles).
  • Mushroom exposure from the genus Amanita (fungi, toxins). These are most common in Europe but also occur in North Africa, Asia and parts of the United States.

Blood Sampling

  • S-paracetamol/acetaminophen
  • Toxicological screening in urine (amphetamine, ecstacy etc.) + other acute intoxication samples in serum according to local routines (ethanol, s-salicylate, etc.). If strong suspicion of special sampling for synthetic internet drugs (urine/blood)
  • S-Fe, S-TIBC and S-Ferritin (Hemochromatosis)
  • Ceruloplasmin, (tU-Copper – Wilson’s disease)
  • Arterial blood gases + intensive care tests including coagulation tests and liver status, etc.
  • Blood cultivation (aerobic + anaerobic)
  • Urinary culture and microscopic analysis of urine
  • Autoantibodies: ANA (antinuclear antibodies), SMA (smooth muscle antibodies) and AMA (mitochondrial antibodies)
  • Alpha 1-antitrypsin

Viral Hepatitis

  • Anti-HAV IgG, IgM
  • HbsAg: about positive: take HBV DNA quantitatively, anti-HDV, (HBeAg, anti-HBE)
  • Anti-HBc IgM: on positive HBV DNA quantitatively
  • Anti-HCV: To positively take HCV RNA quantitatively (sometimes it is recommended that HCV RNA be taken
  • Immediately because Anti-HCV may be negative early).
  • Anti HEV IgG: on postive PCR HEV in blood and stools.
  • Anti-EB IgG, IgM (Ebstein-Barr)
  • Anti-HSV 1 and 2 (Herpes Simplex)
  • Anti-VZV (Varicella Zoster Virus)
  • Anti CMV IgG, IgM
  • HIV serology
  • (Parvovirus B19 IgG, IgM)

Clinical Investigation

  • Ultrasound of the liver with doppler for the assessment of liver parenchyma and blood flow to and from the liver (hepatic artery and veins)
  • CT abdomen to determine any ascites or malignancy
  • UCG (echocardiography)
  • Chest X-ray
  • CT-scan brain

Prognostic Assessment

Hepatologists at King’s College Hospital  in London have developed prognostic criteria  for indication of liver transplantation (O’Grady et al. 1989). Many have tried to assess the performance of the KCH criteria. The largest meta-analysis has revealed that the KCH criteria for non-paracetamol-induced liver damage have a sensitivity of 68% and a specificity of 82%. The KCH criteria have a sensitivity of 58% and specificity of 95% in paracetamol-induced liver damage. The balance is difficult between missing patients who survived with transplant and patients who would still survive without transplantation.

King’s College Criteria for performing Liver Transplantation at ALF

In case of paracetamol induced liver damage:

  • Arterial PH < 7.30 after fluid resuscitation or all of the following:
  • PK/INR > 6.5
  • S-Creatinine > 300 micromol/l
  • Encephalopathy grade 3/4

In the case of non-paracetamol-induced liver damage:

  • INR > 6.5 or at least three of the following:
  • NANB (unknown)/drug/halothane etiology
  • Debut encephalopathy > 7 days after icterus debut
  • Age <10 or > 40 years
  • INR > 3.5
  • S-Bilirubin > 300 micromol/l

MELD Score

A short-term survival predictor (months) is the Model of End Stage Liver Disease Score (MELD), calculated on the basis of the values ​​of bilirubin, INR and serum creatinine. It is used to assess the need for liver transplantation.

The 3-month survival is:

  • 90% at MELD Score 20
  • 60% at MELD Score 30
  • 10% at MELD Score 40

The formula for MELD is: = 9.57 x log e (Creatinine mg/dL *) + 3.78 x log e (Bilirubin mg/dL **) + 11.20 x log e (INR) + 6.4

* Creatinine 1 mg/dL = 88.4 micromol/L. ** Bilirubin: 1 mg/dL = 17.1 micromol/L

Meld calculators on the Internet make it easier to calculate MELD, for example: Click here for link to MELD calculator

Level of Care

Patient with ALF and Encephalopathy grade 2 (Modified Parsons-Smith Scale) (Compatible with GCS 11-14) is treated in an intensive care unit. You can be contacted from other hospitals regarding this patient group at a transplantation center for the assessment of liver transplantation. If the patient develops hepatic encephalopathy grade 3-4, it may be complicated or impossible to transport the patient between hospitals due to the high risk of respiratory failure or unconsciousness.

Responsibility of Care

At a transplant center, the patient is assessed by a team of:

  • Hepatologist
  • Transplantation surgeon
  • ICU physician
  • Transplantation anaesthesiologist

Treatment of ALF

The aim of the medical treatment is to support vital functions and create conditions for hepatocyte regeneration, oxygenation and optimize the patient for liver transplantation.

Treatment Recommendations

  • Infusion of acetylcysteine ​​as follows: 350 mg/kg in 100 ml NaCl 0.9% in 15 min followed by 50 mg/kg in 100 ml NaCl 0.9% in 4 hours. Then 100 mg/kg in 200 ml NaCl 0.9% in 24 hours. The treatment should be started already at the local hospital. Evidence exists that acetylcysteine ​​also has an effect on non-paracetamol-induced liver damage if encephalopathy is < 3 and the patient is adult. The treatment with acetylcysteine ​​lasts for a maximum of 5 days. Begin infusion of acetylcysteine ​​according to protocol as soon as possible.
  • Early start of venovenous continuous hemodialysis (CRRT) preferably with CVVH setting and high flow rates.
  • Ammonium ion in arterial blood is followed.
  • S-Sodium should be kept high to reduce the risk of brain edema. If encephalopathy grade> 3, S-sodium levels are recommended between 145-155 mmol/l.
  • If hypoglycaemia common to ALF develops give 10-20% glucose solution iv. ALF is a catabolic state.
  • Enetral Nutrition (EN) is recommended without protein restriction (1-1.5 g/kg/day). Calorie content of 600-800 kcal/day first week is considered appropriate. Vitamin deficiency is common in ALF and must be replaced.
  • Phytomenadion (Konakion) 10 mg x 1-2 i.v.
  • Ulcus prophylaxis (omeprazole) with inj. omeprazole 40 mg x 1 iv.
  • Lactulose is no longer recommended for ALF because of dehydration risk
  • Antibiotic prophylaxis (broad spectrum a-b) with e.g. meropenem and a fungicide. First of all, Ecalta (anidulafungin) because it has minimal liver effect (200 mg day 1, then 100 mg per day).
  • Antiviral therapy in detected viral hepatitis. If ALF is suspected of being caused by Hepatitis B, treatment must be initiated immediately and this will probably also apply to Hepatitis C now when we get access to new antiviral agents.
  • “Seizure prophylaxis” should be considered if the patient is on a ventilator and no EEG is available.

Monitoring

The patient usually needs invasive monitoring. Coagulopathy in liver failure contains both prothrombotic and antithrombotic components. The INR value in liver failure is rarely associated with increased bleeding risk. Thromboelastogram (Rotem) may be helpful (normal in 45%, hypercoagulable in 35% and hypocoagulable in 20%). One should avoid giving plasma administration if possible, as this further complicates the development of liver failure. Factor concentrate type ocplex increases the risk of thrombotic complications. Plasma, fibrinogen and platelets are only recommended for active bleeding or when inserting intracranial parenchyma catheters for measurement of intracranial pressure (ICP). Temporary correction of coagulation lasts for only 2-6 hours and thrombotic complications are possible during this time. Arterial line, central venous line, nasogastric tube, bladder catheter with urinary output. Hemodynamic monitoring with e.g. PICCO at circulatory instability is common in ALF. PA catheter may be considered. ICP measurement may be relevant (greatest risk of brain edema in hyperacute and acute ALF). Daily blood sampling: (some sampling is taken several times/day, prescribed in the individual case) Hgb, white blood cells, TPC, CRP, ProCalcitonin, Sodium, Potassium, Phosphate, Magnesium, Calcium, Creatinine, Urea, Albumin, Liver parameters, INR, β-amylase, APT Time, Antithrombin III, Fibrinogen, D-Dimer, TEG, Repeated arterial blood gases: β-glucose, lactate, ammonium ion are followed. Daily total body weight.

Special monitoring and treatment

In the case of ALF, the two most common causes of death are:

  • Sepsis with MOF
  • Brain edema with cerebral infarction (previous common cause of death (before 1990))

Survival in ALF patients has improved significantly over the last 4 decades. This has been possible with improved medical care and liver transplantation when needed. Applies especially to the hyperacute and acute group of ALF. In the subacute group, survival is still low without transplantation. The natural course of ALF has changed since sepsis now occurs later in the process and fewer patients develop brain edema with intracranial pressure increase. In patients with subacute disease, low grade encephalopathy may also indicate very poor prognosis, while in patients with hyperacute disease, survival with medical care may be high even in patients with high grade encephalopathy.

CNS

Cerebral edema with intracranial hypertension affects 20% of patients with ALF (2004-2008). Most common in hyperacute and acute ALF. Hyperammonemia and high concentration of organic osmolytes in the astrocytes are of central importance in pathophysiology. Systemic inflammation and recurrent infections together with hyperammonemia accelerate the development of brain edema. Both clinical symptoms and CT brain are unspecific. With sustained ICP over 30 mm Hg, besides consciousness reduction, agitation, systolic hypertension, increased muscle tone with stretch cramps, hyperventilation and abnormal pupil reaction can be expected. A rapid progression to deterioration is common.

EEG – Non-convulsive status continuously EEG monitoring is recommended.

Encephalopathy – rate as follows

Modified Parsons-Smith Scale of Hepatic Encephalopathy
GradeClinical FeaturesNeurological SignsGCS
0/subclinicalNormalOnly seen on neuro psychometric testing15
1Trivial lack of awareness, shortened attention spanTremor, apraxia, incoordination15
2Lethargy, disorientation, Personality changeAsterixis, ataxia, dysarthria11-14
3Confusion, somnolence, Semi-stupor, responsive to stimuli, fits of rage
Asterixis, ataxia8-10
4Coma+- Decerebration <8

Patients with ALF may decline within a few hours from encephalopathy 1 to grade 3 or 4 with severe intracranial pressure increase. It is therefore important to regularly assess the rate of encephalopathy. Pupil control should be done every hour if the patient is unstable.

ICP measurement may be considered in the following cases: (greatest risk of brain edema in hyperacute and acute ALF).

  1. If the arterial ammonium ion is more than 150 micromol/l for more than 24 hours.
  2. In case of pronounced hyponatraemia (less than 130 mmol/l)
  3. Abnormal pupil reflexes or precense of seizures
  4. Encephalopathy 3-4 or when the patient is placed in the respirator.
  5. Three out of four SIRS criteria
  6. ALF patient who needs vasopressor and develops kidney failure

Neurosurgeon may insert ICP monitors as needed (parenchymeters can be placed epidurally to minimize bleeding risk). The patient receives plasma, platelets and fibrinogen immediately prior to surgery. Target values ​​for coagulation are prescribed in the individual case. Sampling for INR, APT time, fibrinogen, platelets, TEG and possibly multiply before the procedure. Seek the ICP below 20 mmHg and CPP over 55 mmHg.

Measures to prevent high ICP

  1. Keep high serum tonicity (S-Sodium 145-155 mmol/L)
  2. Early CRRT with high flows (CVVH setting). Follow ammonium ion.
  3. Elevate head end to 30 degrees.
  4. Normovolemia
  5. Normoventilation with adequate oxygenation (PO2 > 12 kPa).
  6. Β-glucose 6-8 mmol/l
  7. Normal temperature
  8. Adequate sedation: Sedatives such as Propofol/remifentanil facilitate assessment of the degree of consioussness.

In case of ICP/CPP problems – Gain time for life saving acute liver transplantation

  1. Increase sedation: induces hypometabolic vasoconstriction in the brain
  2. Give hypertonic sodium solutions all. mannitol (hypertonic sodium solution is preferred because BBB is less permeable for, for example, rescue flow due to its higher osmolarity compared to mannitol) (resorption coefficient 1.0 for hypertonic sodium compared to 0.9 for mannitol).
  3. CRRT with high flow CVVH. Lowers circulating ammonium ions. Avoid dysequilibrium by adding sodium in dialysis fluids corresponding to S-Na in the patient (should be 145-155). give hypertonic sodium solution iv.
  4. Induce mild hypothermia: (may, however, have other negative consequences eg poorer coagulation, etc.)
  5. Hyperventilation to gain some time.
  6. NSAIDs (indomethacin 0.5 mg/kg iv) may be considered in manifest intracranial hypertension with documented cerebral hyperemia.
  7. Barbiturates are not recommended for ALF with high ICP but may be tested for therapy-resistant intracranial hypertension.

Respiration

Early elective intubation with respiratory care may be applicable already prior to transport to the Transplantation Unit. However, the usual one is that the patient is unintentional to facilitate assessment. In literature, intubation is recommended at Encephalopatigrad> 2. Note that these patients have high aspiration risk. Sedea patients with cardiovascular agents (remifentanil / propofol) to facilitate assessment even after intubation. PEEP levels below 10 mmHg and standard ventilation are recommended.

Circulation

Hemodynamically unstable is common in ALF. Characteristic is a pronounced vasodilation with hypotension and hyperdynamic increase of CI. At the microcirculation level, oxygen uptake is disturbed with abnormal shuntar. Hyperlacticemia is common. The recommendation in the literature is:

  1. Keep MAP> 65 mmHg
  2. Give volume such as Albumin in the first place, crystalloids in the other hand, avoid starch solutions.
  3. If vasopressors are needed for adequate MAP, norepinephrine is the first choice.
  4. Terlipressin can be added as needed.
  5. Expand hemodynamic monitoring when needed (PICCO, Swan-Ganz, etc.).
  6. In therapy-resistant hypotension, hydrocortisone may be tested.

Kidneys

Acute renal failure is a common complication to ALF. The cause is considered to be multifactorial with causes such as sepsis, SIRS, hypovolemic renal hypoperfusion, drug-induced nephrotoxicity (eg aminoglycosides, X-ray contrast agents and acetaminophen), cadmium release from necrotic liver and finally intraabdominal hypertension. Prevention of renal failure is important by removing nephrotoxins, limiting intravenous contrast, maintaining adequate MAP, and maintaining adequate circulating volume.

The literature recommends the following in case of renal failure as a complication of ALF:

  1. Keep MAP > 70 mmHg (slightly higher than the above recommendation).
  2. Try to avoid positive fluid balance.
  3. Measure abdominal pressure
  4. At oliguria despite optimal plasma volume and MAP, early start of CRRT is recommended, preferably in CVVH mode. (With us CVVHDF with 0 in dialysate).

Coagulopathy

Check the coagulation with extended specific sampling. Use TEG and possibly. “Multiplate” for graphical monitoring. Platelet concentrate and fibrinogen may need to be given prior to invasive surgery.

Infection Control

This patient group is highly susceptible to infection and a serious infection within a couple of days is more rule than exception. ALF patients are very susceptible to bacteria and fungal infections. There is a low threshold for antibiotic startup at ALF, but prophylactic antibiotics have unfortunately not proven improved survival. Often, there are no classic signs of infection such as fever and leukocytosis. CRP and procalcitonin may be of value but no inflammation parameter can be trusted in full. Praxis is after all prophylactic broad spectrum antibiotics with Meronem and fungicides, preferably anidulafungin (Ecalta), which has low liver toxicity and does not need dose adjustments for liver or kidney failure. Alternatives are Mycamine (Micafungin), which however needs dose correction in severe liver failure. A well-proven fungicide is otherwise Ambisome (Amphotericin B). Infection primarily recommends Ecalta in case of severe liver failure (of course, treatment should be governed by cultivation response with resistance determination.

MARS (Molecular Adsorbent Recycling System)

In a French controlled multicentre study (Saliba, Camis, Durand et al) on ALF, there was no evidence of increased survival with MARS. The majority of patients received only one treatment because they were transplanted within 24 hours. In a subgroup analysis there was a tendency for increased survival of paracetamol-induced ALF. Transplant-free survival was significantly longer in those patients who received at least three MARS treatment cycles.

In a Finnish study on ALF (Kantola et al) (113 patients between 2001-2007 compared to a control of 47 patients between 1995-2001). Here, a survival gain with MARS was also shown on transplanted patients treated before transplantation. However, the improvement has been assessed as a consequence of the development of intensive care, anesthesia and surgical techniques, rather than because of. MARCH in itself. However, the RELIEF study performed on the AoCLF patient group did not show any increased survival with MARS. Encephalopathy enhancement, however, was significant.

High Volume Plasma Exchange

Preliminary studies show promising results. Sixteen percent of body weight is replaced by plasma pharynx every day for three days (Fin Stolze Larsen, Copenhagen). Soon, a study will be published which, according to abstract, shows 20% survival gain in a non-transplant group but treated with high volume plasma phases. May be the first temporary delivery support system that shows significant survival gains at ALF.

“Urgent Call” for liver transplantation

At ALF or in case of early retransplantation after liver transplantation, it is possible to put the patient on the waiting list for liver transplant with urgent call request within the framework of Scandiatransplant. Urgent call means that the patient has priority for the first appropriate (blood group-compatible) donor in the Nordic region. This priority is for three days. If two “urgent patients” are out at the same time, the one who first came out has priority. Once the three days have elapsed, transplanting clinics have the opportunity to make an appeal, which in most cases is usually respected.

Note that “urgent call” can not be used for patients with chronic liver failure. Indications for acute retransplantation may be “primary non function” (arterial thrombosis, venous thrombosis or severe rejection). There is no defined time interval after the transplant here, but this is an assessment question in each case. The setting of the patient on the waiting list as urgent call is done by the responsible transplant surgeon.

References

  1. Acute Liver Failure Lancet 2010;376:190-201. W Bernal, G Auzinger, Julia Wendon.
  2. Acute Liver Failure NEJM 369;26 NEJM.ORG December 26, 2013 W Bernal, J Wendon.
  3. Critical Care in Acute Liver Failure (Roger Williams and Julia Wendon) 2013. Future Medicine. ISBN: 978-1-78084-257-8
  4. Acute hepatic failure (PACT 2012) Chris Willars and Julia Wendon.

Diabetes Mellitus – Perioperative Care

Posted by Ann-Charlotte Loswick, Senior Physician in Anesthesia & Intensive Care. Sahlgrenska University Hospital.
Updated 2019-06-13


Background

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

Poorly regulated diabetes involves an increased risk of complications with worse wound healing, higher infection risk and risk of hypoglycaemia associated with anesthesia and surgery. In case of elective intervention, normalized metabolic control should be sought.

HbA1c is a long-term measure of glucose levels. Target value for HbA1c is 52 mmol / mole, reducing the risk of complications. HbA1c is a form of hemoglobin (glycated hemoglobin) whose measurement value provides an average of how blood sugar has been a time back (1-3 months). HbA1c is measured in mmol / mol.

If patients have preoperatively P-Glucose over 15 mmol / L, this should be corrected before surgery. In acute operations, normoglycemia is sought pre- and postoperatively. If the patient is over 80 years of age, avoid lowering blood sugar and, above all, avoid hypoglycaemia.

Target value for perioperative β-glucose is 4-12 mmol/L.

There are several different types of insulin. Basic Insulin is usually meant medium or long acting insulin. Meal insulin means direct or short acting insulin.

Different Types of Insulin

Perioperative Care of Patients with Diabetes Mellitus

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 insulin (Actrapid and Humulin regular) and insulin analogues (Apidra, Humalog and Novorapid).

  • Human insulins begin to work within 30 minutes, have maximum effect after about 2 hours and a total duration of 5-7 hours.
  • Insulin analogues start to work already after 10-15 minutes, have their maximum effect after about 1 hour with a total duration of 3-4 hours.
  • The longer duration of human insulin is preferred to insulin analogues in the ICU and postop.

Medium Acting Insulin (NPH)

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

Long Acting Analogues

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

Mixed Insulin (Mix)

All mixed insulins are is a ready blend of medium-acting (NPH) and short-acting insulin analogues (Humalog 25, Humalog 50 and Novomix 30). The figure indicates the percentage of short acting insulin analogue.

Guidelines for Perioperative Treatment of Diabetes

1. Dietary Controlled Diabetes

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

2. Tablet Controlled Diabetes

Diabetes mellitus - Tablet Controlled Diabetes

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

3. Insulin Treated Diabetes

Diabetes Mellitus - Insulin Treated Diabetes

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.

4. Patients with an insulin pump. Typ 1 Diabetes. Fast acting Insulin.

Diabetes Mellitus - Patients with Insulin Pump

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 can not be obtained postoperatively with the above regimen, special diabetologist should be consulted. Follow-up should be done with a new measurement of HbA1c.


Posted by Johan Wersäll, Physician in Anesthesia & Intensive Care, Sahlgrenska University Hospital.
Updated 2019-06-13


Diabetic Keto Acidosis (DKA) is an acute complication of diabetic mellitus due to 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 anti-regulatory hormones glucagon, catecholamines, cortisone and/or growth hormone in relation to the body’s insulin requirements. Both situations may lead to DKA, which means metabolic acidosis, dehydration and electrolyte imbalances. DKA can occur both in type 1 and type 2 diabetes. Patients need urgent and consistent treatment and initially ICU care may be required.

Pathophysiology

Insulin acts as an anabolic hormone that, among other things, opens glucose transport to most cells, increases glycogenesis in liver cells and muscle cells, inhibits gluconeogenesis, and reduces fat degradation by inhibiting enzyme lipase. Glucose levels are usually within narrow ranges, between 4-5.6 mmol/L, and regulated by endocrine pancreas stimulated to increase insulin secretion at increasing glucose levels. Most of the body’s cells need insulin to pass glucose across the cell membrane in meaningful concentrations and then be used for ATP production. However, nerve cells are an important exception that does not require insulin for glucose transport, which is why the brain’s metabolism needs can be satisfied despite insulin deficiency.

In absolute or relative insulin deficiency, the opposite of the effects of insulin occurs: hyperglycaemia occurs when glucose remains outside cells and the glycogen is broken down; Protein degradation and additional hyperglycemia are added via increased gluconeogenesis; free fatty acids accumulate via the increased lipase activity, which first converts acetyl coenzyme A and then into ketone bodies (acetone, beta-hydroxybutyric acid and acetoacetate) in the liver. The process causes osmotic diuresis and vomiting which leads to dehydration and electrolyte losses, as well as accumulation of acid ketone bodies and poor peripheral perfusion leading to metabolic acidosis (see figure). Without insulin treatment, the condition of adults will lead to death via 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 have not been established.

The biochemical criteria for the diagnosis of diabetic ketoacidosis are:

  • Hyperglycaemia (P-Glucose > 11 mmol/L)
  • Venous pH < 7.3 or S-Bicarbonate < 15 mmol/L
  • Ketonemia and/or ketonuria (blood ketones above ≥ 3 mmol/L)

Treatment

The most important treatment is fluid, insulin and adequate potassium supply.

Fluid Rehydration

There is no strong evidence of differences between Ringer’s Acetate and Sodium Chloride in time to acidified acidosis. Studies have shown that the risk of cerebral edema increases if measured P-Sodium does not increase after treatment start, and the goal is to keep sodium within the normal reference range. So-called pseudohyponatremia is common in ketoacidosis due to the dilution effects of hyperglycemic, and can be corrected by the formula:

P-Sodiumcorrected = P-Sodiummeasured + 2.4 x [(β-glucose-5,6)/5,6]

(Ex. measured P-Sodium 129, P-Glucose 30 mmol/L: P-Sodiumcorrected = 129 + 2.4 x [(30-5.6)/5.6] ≈ 139 mmol/L)

In the case of pronounced corrected hyponatremia (Sodiumcorrected < 130), Sodium Chloride should be chosen while Ringer’s Acetate is good in other cases.

Insulin

The only treatment that can relieve diabetic ketoacidosis is insulin. However, note that insulin therapy must be preceded by fluid therapy! Insulin infusion may begin after one hour of rehydration and usually with potassium except for severe hyperkalemia (Potassium > 5.2 mml/L). A smooth infusion rate of 0.1 units/kg can be started without insulin bolus.

Potassium

The patient is always hypokalemic and potassium is given at P-Potassium <5.2 at infusion rate 10-20 mmol/h. Due to the acidosis, apparent hyperkalaemia can often be seen. As a benchmark, potassium concentration increases with 0.6 mmol/L for each 0.1 as pH decreases but large variability occurs (0.2 – 1.7 mmol/L) and most importantly, remember that these patients would have hypokalaemia if the pH was normal. In the case of insulin delivery, potassium will be displaced into the cells, thus keeping track of potassium levels with frequent blood gas controls.

Buffering?

Buffering generally has no place in the treatment of DKA but may be considered in adult patients at pronounced acidosis with pH <6.9 after initiation of fluid therapy. In that case, it is extra important to keep track of potassium levels that can drop quickly and strongly.

In children, buffering is contraindicated as this is shown to increase the risk of cerebral edema despite pronounced acidosis!

Cerebral Edema

Clinical manifestation of cerebral edema is a rare but serious complication of DKA in children with a mortality rate of 20% -50%. Signs of cerebral edema usually occur 4-24 hours after treatment start. Risk factors are:

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

Treatment with mannitol or hypertonic saline (3% Sodium) is initiated in suspicion of cerebral edema and Muir’s criteria can serve as guidance for treatment decisions.

References

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


Hyperkalemia

Posted by Kai Knudsen, Senior Physician in Anesthesia & Intensive Care, Sahlgrenska University Hospital.
Updated 2019-06-13


Hyperkalemia usually occurs at cellular degradation, metabolic acidosis, acute or chronic renal failure, critical ischemia, Addison’s disease, in shock or after ingestion of potassium or potassium-sparing diuretics. Dehydration and starvation are other conditions that can cause severe hyperkalemia. In case of pronounced hyperkalaemia there is a risk of severe cardiac arrhythmias, ventricular fibrillation and circulatory collapse. Investigation and treatment must capture and correct underlying causes, but at the S-potassium values ​​above 6.0 mmol/l, treatment should be introduced as soon as possible. Here are suggestions on different forms of treatment. In the case of a patient with hyperkalemia, surgery should be postponed and the hyperkalemia should be preoperatively corrected at values ​​above 5.5 mmol/L if possible.

Treatment of hyperkalemia

  • Calcium: At QRS and S-K > 6.0 mmol/L: Administration of calcium, 10 ml Calcium-sandoz 9 mg/ml in 1 min – repeat until ECG is normalized.
  • Intravenous fluid: Dilute the plasma volume with Sodium Chloride 9 mg/ml 1000-2000 ml.
  • Glucose Insulin administration: 20 E Actrapid/Novorapid in 500 ml 10% glucose, give 250 ml in 15 min. Follow P-glucose and blood gases. Effect after about 15 minutes, usually later.
  • Sodium Bicarbonate at acidosis: 100 ml i v – gives immediate effect, can be repeated. Lowers potassium by about 0.5 mmol/L
  • Salbutamol (Bricanyl) (beta-2 stimulator): 0.5-1 mg for 15 minutes. 1 mg is added in 100 ml SodiumChloride, given for 30-60 minutes, following the pulse.
  • Resonium: Sodium polystyrene sulfate, cation exchanger. 15 g x 3-4. Effect after 1-2 hours, given rectally or per os.
  • Magnesium: 20 mmol in v (caution in hypotensive patients) for 20 min.

 

  •  

Hypokalemia

Posted by Kai Knudsen, Senior Physician in Anesthesia & Intensive Care, Sahlgrenska University Hospital.
Updated 2019-06-13


Definition: S-Potassium <3.5 mmol/L

Symptoms and findings

Rarely symptoms until β-potassium is less than 3.0 mmol/L (coupled to increased gradient of membrane potential, ie in all muscles)

Symptoms of hypokalemia: muscle weakness, decreased peripheral reflexes, ileus/subileus, ECG changes (decreased ST-segment, decreased T-wave and U-wave presence) and increased fatigue. Cases of neuromuscular disease, critically ill patients, decreased GFR, impaired concentration in the kidney with polyuria may be particularly sensitive to hypokalaemia.

Causes of Hypokalemia

Renal lossNon-Renal Causes
With HypertensionWith normal blood pressure
Cushing syndromRenal tubular acidosisAlkalosisIntestinal losses
Congenital adrenal hyperplasiaFanconi syndromeLeucemiaDiarrhéa
Primary hyperaldosteronismBartter's syndromFamiliar hypokalemic periodic paralysis Laxatives
Increased amount of reninDiabetic keto acidosisSweatingEnema
Renovascular diseaseAntibioticsAnorexia nervosa
DiureticsEnterocutanous fistula  
Alcoholism
Urinary K > 20 mmol /LUrinary K < 20 mmol /L

Diagnostics and investigation

Depending on the clinical picture and the underlying cause:

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

Treatment and follow-up

Addition of potassium 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, usually 20-40 mmol/L. If higher concentrations are desired, the infusion must be labeled and given in a central venous catheter (CVC). This is to avoid dangerous and rapid infusion of potassium. If necessary, the supply may be increased, but the maximum rate is 0.5 mmol/kg/hour (max 20 mmol/h to adult patient). In such cases, the infusion must for safety reasons go into separate needle/lumen where there will be no other infusion or other medicines. At high rate of infusion, s-potassium must be followed with frequent blood samples. Strong potassium solutions are highly tissue-irritating to veins, skin and subcutaneous tissue, and should be given through central catheters. Extensions where potassium infusions goes must not be dressed during surgery so that the entry is hidden during ongoing anesthesia.


Hyponatremia

Posted by Hanna Drougge, Specialist Physician in Anesthesia & Intensive Care, Sahlgrenska University Hospital.
Updated 2019-06-13


Background

Hyponatraemia (s-Na <135 mmol/L) is the most common electrolyte disorder and affects 15-30% of hospitalized patients. It leads to increased mortality, morbidity and prolonged care times. Hyponatremia is not primarily a pure sodium deficiency but a relative excess of water. When acute hyponatremia occurs, there is a risk of cerebral edema when fluid passes intracellularly when blood osmolality decreases. The brain needs about 48 hours to adapt to the hypotonic environment. When this has occurred, the risk of brain edema is smaller, instead, the risk of osmotic demyelinating syndrome increases if serum sodium is increased too fast. This is because the myelin skins that isolate the neurons can be damaged in case of a rapid osmolality shift. This is the background to why it is important to separate acute from chronic emerging hyponatraemia before correcting starts.

Common causes of hyponatraemia include SIADH, diuretics, ethyl alcohol, hyperglycemia, polydipsia, renal failure, drug, hypotonic fluid supply and, to some extent, physical exercise with excessive water intake.

Symptoms

Big variation with everything from mild, unspecific symptoms to very serious life-threatening symptoms with brain edema and clotting. Acute hyponatraemia usually has more pronounced symptoms, whereas hyponatraemia developed over a long period of time may be symptomatic despite very low sodium levels in serum.

Common symptoms include balance difficulties, cognitive failure, headache, nausea, vomiting, cramps, loss of consciousness and confusion.

Investigation

Separate acute hyponatraemia (documented duration <48 hours). In the case of unclear duration, the hyponatremy is assumed to be chronic unless otherwise explicitly speaks for something else, such as long distance running.

Exclude hyperglycaemia as a cause of hyponatremia, as well as other iso / hyperosmolar conditions e.g. administration of mannitol, contrast, urea and intake of different alcohols. These conditions have normal or high serum osmolality and the hyponatremia is secondary.

Blood Sampling for investigation of Hyponatraemia

S-Na, S-K, U-Na, U-K, S-Osm, U-Osm, β-glucose, S-creatinine, liver status, TSH, free T4, S-cortisol.

Assess patient’s volume status according to the following figure (hypo-, hyper- or euvolem?). The figure also indicates common underlying causes of the different states.

Figur 1. Utredning av hyponatremi.

Figure 1. Study of hyponatraemia.

Treatment of hyponatremia

  • Treat underlying disease.
  • Discontinue medicines that may have triggered hyponatraemia.
  • In case of strong clinical suspicion of acute adrenal insufficiency, Mb Addison, treatment with hydrocortisone (Solu-Cortef) and 0.9% NaCl in v should be started.
  • Check other electrolytes and correct if necessary.
  • Correctly correct the hyponatremy.

Chronic hyponatraemia (> 48h) with mild symptoms should first be investigated and underlying causes are treated. Hyponatremine is slowly corrected, aiming to raise sodium with a maximum of 0.5 mmol / L / h, total <8 mmol / L / day. This may be on a wakeful basis, normovolar patients are made by fluid restriction. Hypovolemia is treated with 0.9% NaCl and hypervolaemia with loop diuretics. Calculation of 0.9% NaCl infusion rate is difficult as formulas do not take into account how much sodium is lost through urine etc. The calculation should therefore be seen as a guideline adjusted after sampling depending on how the patient responds to inpatient treatment.

Chronic hypovolemia hyponatraemia where slow correction is planned, an initial infusion rate can be calculated as follows:

  • Target value S-Na 130 mmol/L
  • Measure current S-Na (mmol/L) and weight V (kg)
  • Calculate the amount of body water KV (L), women Weight x 0.5, men Weight x 0.6
  • Determine net increase of S-Na (mmol/L); 130 minus current value;
  • If the planned net increase is> 8 mmol/L: Calculate total time (hr) to reach the target of 0.3 mmol/L/h.
  • If the planned net increase is <8 mmol/L: Calculate total time (hr) to reach the target at 0.5 mmol/L/h.
  • Calculate total Na need (number of mmol); KV (L) x net increase of S-Na
  • Calculate the volume of liquid (L) required; Total Na need (mmol) / Na-konc (mmol / L) in the infusion fluid
  • Calculate the rate of infusion (ml/hr); Planned volume of fluid (ml)/planned number of hours

Severe symptomatic hyponatremia with, for example, seizures must be corrected initially until the serious symptoms disappear. Increase S-Sodium initially at 1-2 mmol/L/hr using 0.9% or 3% NaCl in v. When symptoms decrease, the rate of correction is reduced and the total daily correction should not exceed 8 mmol/L/day.

If acute correction is needed, 3% NaCl 1 ml/kg gives an increase of S-Na with about 1 mmol/L.

Hyperton 3% NaCl is obtained by adding 160 mmol Na (40 ml AddexNa) to 500 ml 0.9% NaCl. Dense sampling if hypertonic saline is given due to risk of overcorrection.

Important with tight monitoring during correction! Initially every hour, which can be spotted when the patient is stable and the increase occurs at the pace as planned. Increased diuresis may indicate reduced ADH impulses and be indicative of rapid correction. Reduce infusion rate and check S-Na.

For quick fix?

– Lower the rate of infusion or turn off

– Give Sodium-free liquid (glucose, water per os/tube)

– In case of large diuresis, desmopressin (Minirin) may be considered. NOTE! Think of the risk of brain edema!

– Reversal, ie, dilution if sodium rises too fast.

References

  1. Chantzichristos et al., Health Care Program for Hyponatraemia, 2012.
  2. Spasovski et al. Clinical Practice Guideline on Diagnosis and Treatment of Hyponatremia. Eur J Endocrinol. 2014 Feb 25; 170 (3): G1-47
  3. Verbalis et al., Diagnosis, Evaluation, and Treatment of Hyponatremia: Expert panel recommendations. Am Journal of Med 126: S5-S42

Malignant Hyperthermia

Posted by Gunilla Islander, Senior Physician in Anesthesia & Intensive Care, Skåne University Hospital, Lund.
Updated 2019-06-13


Advice for the Treatment of an Acute Reaction

Malign Hyperthermia (MH) Sensitivity is a hereditary condition where potent inhalation anesthetics and/or suxametonium can trigger a life-threatening reaction under anesthesia. In an MH reaction, signs of hypermetabolism and muscle impairment are observed. MH reactions are unusual and important to identify, as they are potentially life threatening and cureable. An earlier complication-free anesthesia with MH triggering agents does not exclude MH sensitivity.

Means that can trigger a MH reaction

  1. Potent Inhalation Anesthetics
  • Isoflurane (Forene®)
  • Sevoflurane (Sevorane®)
  • Desfluran (Suprane®)
  • Older Inhalation Anesthetic Substances (Halothane®, Enfluran®, Ether, etc.)
  1. Depolarizing Muscle Relaxants
  • Suxametonium (Celokurin®) (succinylcholine)

Signs of a MH reaction

The clinical signs of an MH reaction can vary widely, from few to many. The process can range from explosive to more “sneaky”. The clinical diagnosis can therefore be difficult to ask. An MH reaction is almost always developed post-operatively under narcosis or in rare cases. No symptom is patogenic omnipotence for an MH reaction. The diagnosis of MH response is an exclusion diagnosis.

Early Signs from Different Organ Systems

Metabolism

Increased metabolism – hypermetabolism (metabolic storm)

  • Signs of increased CO2 production (EtCO2, pCO2), takypnea. The value of CO2 must be set in relation to the minute volume. If kapnography is missing then a high respiratory rate and quickly consumed as well as the CO2 absorbs the suspicion of increased CO2 production.
  • Increased O2 consumption
  • Metabolic and respiratory acidosis
  • Profus sweating
  • Marbled skin

Muscular Rigidity

  • Masseter spasm following delivery of suxameton (Celokurin®). Masseterspasm = “jaws of steel” remaining for two minutes or more.
  • Generalized muscle rigidity. Generalized muscle rigidity usually occurs a bit later in the process

Cardiovascular Symptoms

  • Difficulty tachycardia
  • Arythmia (eg ectopic ventricular stroke, VES in bigemini)
  • Instant blood pressure

Late Signs

  • Fast temperature rise (core temperature). Measure the temperature centrally; rectal, bladder, esophagus or in CVC. The temperature rise is secondary to hyper metabolism ie. elevated temperature is not a first sign.
  • Hyperkalemia. Immediate hyperkalaemia after suxameton administration also gives suspicion of muscle dystrophy, such as Duchennes muscle dystrophy.
  • Strong increase in CK (creatine kinase)
  • Strong increase of myoglobin (plasma/urine)
  • Dark-colored urine (Coca-Cola/port wine-colored) (signs of myoglobinuria)
  • Kidney failure
  • Severe arrhythmias or cardiac arrest
  • Disseminated intravascular coagulation
  • Multiple organ failure
  • Brain death/death

Differential Diagnoses

  • Too light anesthesia
  • Infection/Sepsis
  • Insufficient ventilation or insufficient fresh gas flow
  • Anesthetic failure
  • Iatrogen temperature rise
  • Other neuromuscular disease
  • Anaphylactoid reaction, feochromocytoma, thyroid toxicity, ecstasy or other central stimulant drug reaction, NMS – Neuroleptic Malignant Syndrome.

Treatment

Treatment should be initiated immediately. The dantrol has top priority. Delay in the supply of dantrol increases mortality and morbidity. The symptoms may vary considerably and the treatment will be adjusted accordingly

Immediately

  • Stop the supply of all triggering agents. Lift off the anesthesia gas vaporizer. If it does not shut 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 operating room and call for help. Request to receive the dantrolene. It takes a lot of staff to mix the dantrolene, take samples, arrange accesses, etc.
  • Change to total intravenous anesthesia. Do not waste time here to replace hoses or anesthetics, it can be done later. The dantrolene has top priority.
  • Decide whether or not the operational operation should be completed.
  • If the operator is inexperienced call an experienced colleague.

Dantrolene (Dantrium®)

  • Give dantrolene 2 mg/kg intravenously. Ampoules of 20 mg are mixed with 60 ml of sterile water. It is easiest to use space-tempered sterile water.
  • Repeat delivery until symptoms persist.
  • If there seems to be a lack of dantrolene, seek more from another healthcare institution
  • Maximal doseage dantrolene is 10 mg/kg, but it may in rare cases be exceeded.

Monitoring

  • Continue initiated monitoring (SaO2, EtCO2, ECG, Blood Pressure)
  • Temperature measurement centrally (rectal, bladder, esophagus or in CVC). Peripheral temperature measurement is unreliable in this situation.
  • Ensure that there are good well functioning venous infections.
  • Urinary catheter, arterial line, and CVC may be needed. The supply of dantrolene has a higher priority than CVC and an arterial line initially.
  • Lab tests
  • Blood gas
  • Electrolytes
  • CK
  • Myoglobin
  • Blood sugar
  • Creatinine
  • Liver Status
  • Coagulation
  • In case of other sampling
  • Monitor/care the patient in an intensive care or postoperative department for at least 24 hours following an MH response. Symptoms may recurrence and may require treatment.
  • Compartment syndrome can be developed. Check if necessary.

Symptomatic Treatment

Treat Hyperthermia

High priority.

  • Give 2-3 liters of cold Sodium Chloride, Ringer’s Acetate or similar isotonic fluid.
  • Surface cooling: wet sheet or ice in axillaries and groins.
  • Other methods eg Apparatus for surface cooling (suit) or intravenous cooling.
  • Stop cooling the patient when core body temperature has fallen to ~ 38-38.5o The temperature will drop further after the cooling has ended. In case of excessive cooling there is a risk of rebound phenomena.

Treat Hyperkalemia

High priority.

  • In life-threatening hyperkalemia, give calcium. For example calcium gluconate 10-20 ml to adult.
  • Glucose and insulin iv. If necessary for example 20 IU “rapid insulin” in 1000 ml of 5% Glucose 100-200 ml per hour. More insulin may be needed. Check for hypoglycemia.
  • Hemodialysis may be required.

Treat Arrhythmias

  • Amiodarone (Cordarone®) 300 mg to an adult (3 mg/kg)
  • β blockers in the event of tachycardia remaining
  • Do not give calcium antagonists

Maintain good diures > 2 ml/kg/h 

  • Diuretics eg furosemide or mannitol. Note that each bottle of dantrolene contains 3 g of mannitol.
  • Fluids eg Ringer’s Acetate or Sodium Chloride.

Patients who had a suspected MH response should undergo an MH extended investigation with IVCT assay and mutation assay. IVCT = in vitro contracture test. This test involves taking out a small muscle biopsi that is mounted in an organ bath and exposes to halothane and caffeine as well as stimulus electrically. Only negative mutation test does not exclude MH sensitivity. The patient’s closest relatives should be informed.

References

  1. 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.
  2. Rosenberg H, et al. Malignant hyperthermia: a review. Orphanet J Rare Dis. 2015; 10: ’93.
  3. Hopkins PM, et al. European Malignant Hyperthermia Group guidelines for the investigation of malignant hyperthermia susceptibility. Br J Anaesth.2015 Oct; 115 (4): 531-9.
  4. Hypercalcaemia http://www.internetmedicin.se/page.aspx?id=899 (downloaded 2017-02-26)

There is an iPhone app that might be helpful:

Appstore: MHapp – Malignant Hyperthermia Gunilla Islander 170305 MH device Skåne University Hospital/Lund


Pulmonary Embolism

Figur 1. Utredning och behandling av akut massiv lungemboli.
Figure 1. Investigation and treatment of acute massive pulmonary embolism.


Steroid substitution (glucocorticoid substitution) for surgery

Posted by Katalin Kiss, Senior Physician in Anesthesia & Intensive Care, Sahlgrenska University Hospital.
Updated 2019-06-13


The routine aimed at optimal glucocorticoid substitution prior to surgery in patients on chronic cortisone therapy. The recommendation takes into account the clinic’s routine of giving Betamethasone (Betapred) to postoperative nausea. The goal is to provide proper substitution but reduce the risk of overdose and side effects by comparing biological half-lives and equivalent doses.

Background

Natural and synthetic glucocorticoids are used in the treatment of many diseases. Hydrocortisone, a natural glucocorticoid, is used primarily for substitution in adrenal cortical failure. Other (synthetic) glucocorticoids are more potent (see table above) and are usually given to attenuate immune and inflammatory processes. In the longer term use of cortisone, a dose-dependent downregulation of the corticosteroid cortisol synthesis occurs by inhibiting the pituitary hormonal stimulation of the adrenal glands. There is a large individual variability in glucocorticoid sensitivity whose cause is not known. Variability applies to both effects on basic disease and side effects, including suppression of own cortisol production. Acute severe diseases can also be complicated by cortisol deficiency. Hypotalamus-pituitary adrenal (HPA) reactivity may then be suboptimal in relation to the increased need for cortisol production. All glucocorticoid treatment also gives side effects. Acute adrenal corticosteroid or Addison crisis is a life threatening condition due to the risk of circulation collapse. Glucocorticoids maintain vascular tone in part through regulation of the expression of adrenergic receptors. Vasopressor treatment with catecholamines has a reduced effect without cortisone. Addison crisis may occur in patients with all forms of adrenal cortical failure, although those with primary adrenal corticosteroids are at greatest risk. Poor attention is given to patients with tertiary adrenal corticosteroids (after pharmacological treatment with glucocorticoids) who are infected with another disease or other severe somatic disease where treatment with hydrocortisone stress doses is not provided. This form of adrenal cortical failure is usually a transient form of adrenal cortical failure. The risk of developing tertiary adrenal corticosteroid insufficiency increases with increased dose, longer treatment time and longer half-life for glucocorticoid use. Treatment with inhalations, joint injections, including localized treatment with topical solutions, causes long-term side effects because the absorption of steroids in local therapy is very effective and regularly causes glucocorticoid molecules to enter the circulation.

Pharmacological treatment with glucocorticoids for less than 3 weeks with a maximum dose corresponding to 10 mg Prednisolone/day rarely results in retardation of own cortisol production. Treatment at higher doses and/or for a longer period of time may cause cardiac insufficiency of up to 1 year or more after discontinuation.

NOTE! 5 mg prednisolone for one week may suffice to give adrenal cortical failure to some patients. There is not much scientific support on how much cortisone is to be given to patients on Prednisolone treatment or similar preparations. All patients treated with glucocorticoids that may cause tertiary adrenal insufficiency must be monitored for signs of adrenal insufficiency regardless of dose. Unexpected circulatory instability perioperatively may indicate that adrenal glands cannot respond to increased need.

Substitution treatment

Recommendation of substitution for patients at ≥ 5 mg prednisolone/day or equivalent dose of other glucocorticoids.

A. Elective Surgery, short procedures, when the patient has taken a regular dose.

  • No substitution required

B. Elective Surgery, medium size/large surgery, or short surgery but the patient has not taken his regular dose, cannot swallow or have suspected reduced uptake from the intestine.

  • See treatment schedule 1 or 2

C. Acute Surgery, whether or not the patient has taken his or her usual dose.

  • See treatment schedule 1 or 2

Treatment schedule 1

Patients treated with glucocorticoids for immunomodulatory purposes.

Day of operation

Option 1: Betametason (Betapred®) 4 mg intravenously at start of operation*

Option 2: Prioritized to patients with diabetes: 50 mg hydrocortisone (Solu-Cortef®) intravenously in bolus dose at start of surgery. Thereafter 50 mg of hydrocortisone are given every 6 hours, thus a maximum of 200 mg during the surgery day**.

Subsequent Postoperative Days

  • Return to regular medication
  • In perioperative complications, individual assessment is required

* Betametason is routinely used in Sweden to prevent nausea.

** The biological half-life of Betapred® is long, therefore patients with e.g. diabetes, primarily should receive hydrocortisone (Solu-Cortef) to reduce post-operative blood glucose increase.

Treatment schedule 2

Patients with the following conditions:

a) Primary adrenal corticosteroid insufficiency (Addison’s disease)

b) Secondary adrenal insufficiency (pituitary or hypothalamic disease with ACTH insufficiency)

Day of operation

  • Give 100 mg Hydrocortisone (Solu-Cortef®) i.v. in bolus before surgery
  • Then, 50 mg of Hydrocortisone are given every 6:th hour (every 4 hours).

Subsequent Postoperative Days

  • Give hydrocortisone, eg in descending dosage, eg. 50 mg x 2 (-4).
  • Return to normal oral substitution usually occurs postoperative day 2-3
  • In perioperative complications, individual assessment is required.
  • Contact endocrinologist for high risk patients preoperatively
 Equivalent doses (mg)**Glucocorticoid (antiinflammatory) potentialMineral Corticoid PotentialBiological Half-time (hours)
Hydrocortisone20128 - 12
Prednisolone54118 - 36
Methylprednisolone45018 - 36
Betapred0.7530036 - 72
** Thus, equivalent doses (mg)
100 mg Hydrocortisone (Solu-Cortef) = 25 mg Prednisolone = 3.75 mg Betapred

100 mg HYDROCORTISON (Solu-Cortef®) = 25 mg PREDNISOLON = 3.75 mg BETAPRED® 

  • Hydrocortisone (Solu-Cortef®). Dosage: 50-100 mg intravenously. Then 50-100 mg x 2-3.
  • Betamethasone (Betapred®) water-soluble glucocorticoid. Dosage: 4 mg preoperative in acute surgery, then 2 mg x 4 working day and first postoperative day.
  • Methylprednisolone (Solu-Medrol®). Dosage: In shock, 30 mg/kg is slowly administered intravenously. Often, 500-1000 mg is given i v in bolus. In brain edema, 40 mg x 4 is given.
  • Dexametason. A synthetic corticosteroid with predominantly glucocorticoid effect, antiemetic. Dosage: 8-16 mg p o as treatment. Standard dose: 8 mg x 1 p o at PONV.

References

1. Peri-operative steroid supplementation. Nicholson G1, Burrin JM, Hall GM. Anesthesia. 1998 Nov; 53 (11): 1091-104.

2. Perioperative Steroid Management: Approaches Based on Current Evidence Melanie M. Liu, M.D .; Andrea B. Reidy, M.D .; Siavosh Saatee, M.D .; Charles D. Collard, M.D. Anesthesiology 7 2017, Vol.127, 166 172.doi: 10.1097/ALN.0000000000001659


Heparin Schedule Treatment

Posted by Kai Knudsen, Senior Physician in Anesthesia & Intensive Care, Sahlgrenska University Hospital.
Updated 2019-06-13


Heparin, which is usually found in the body complexed bound to proteines, is a highly acidic, sulphated glucosaminoglucan (mucopolysaccharide) with anticoagulant effect. In combination with the co-factor, antithrombin III, heparin affects several steps in the coagulation mechanism, which causes an anticoagulant effect. Heparin is given in the treatment of thromboembolic events such as pulmonary embolism or deep vein thrombosis.

Dosage

  • In the treatment of deep vein thrombosis, a bolus dose of 5000 E (1 ml) i.v. weighing less than 85 kg.
  • At a weight of more than 85 kg, a 7500 E (1.5 ml) bolus is given i.v. In the treatment of pulmonary embolism, a bolus of 7500 E (1.5 ml) i.v.
  • At massive DVT/PE: larger bolus (100-150 E/kg).
  • At increased bleeding risk, a bolus of 2500 E i.v. is given, except for massive pulmonary embolism/DVT.
  • In case of suspected pulmonary embolism, bolus and infusion are given pending the diagnosis. Subsequently, a continuous infusion of heparin, heparin body is given. 15000 E (3 ml) are added in 500 ml 0.9% NaCl or 7500 E (1.5 ml) in 250 ml 0.9% NaCl. The droplet is started at the same time as the bolus dose.
  • At weight > 60 kg and age <65 years, 42 ml/h is given. Other adults are given 36 ml/h. The treatment effect is monitored by APTT controls. First APTT check after 6 hours. APTT should be 1.5-3 times the reference value, that is, 60-120 sec (at increased bleeding risk 50-80 sec).

Heparin Dosing Schedule

aPTT value without increased bleeding risk (target value 60-120 sec)aPTT value at increased bleeding risk (target value 50-80 sec)Primary actionAdjust the drop rateNew sample checked
> 200 sec >160 secCheck 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/hNew test after 4 hours
181-200 sec141-160 secReduce at 9 ml/hNew test after 6 hours
141-180 sec111-140 secReduce at 6 ml/hNew test after 6 hours
121-140 sec81-110 secReduce at 3 ml/hNew test after 6 hours
60-120 sec 50-80 secUnchanged infusion rateIf the first value after drip start, take a new test after 6 hours, or after 12 hours.
50-59 sec 40-49 secIncrease at 2 drops/min (= 6 ml/h)New test after 6 hours
< 50 sec < 40 secGive 2500 E of Heparin i.v. andIncrease infusion rate at 9 ml/hNew test after 6 hours

Indication

Anticoagulation. Deep vein thrombosis (DVT), pulmonary embolism. Intravasal coagulation, peritendinitis crepitans. Extracorporeal circulation associated with cardiovascular surgery and hemodialysis.

Side effects

Haemorrhage, thrombocytopenia, transient liver effect.

Concentration

5000 IU/ml, 25,000 IU/ml.

Caution

Heparin is contraindicated as there is a high risk of bleeding. Caution is advised in the event of thrombocytopenia and platelet function defects (including drug-induced) and severe liver and renal insufficiency.


Sedation in the ICU

Remifentanil 50 μg/ml iv

  • Indication: sedation lasting more than 3 days and preferably to patients with kidney or liver failure or 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

Fentanyl 20 mg/ml iv

Maintenance dose for sedation at 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 may be given as a rapid infusion of approximately 1 μg/kg/minute for the first 10 minutes followed by an infusion of approximately 0.5 μg/kg/h. Alternatively, the loading dose of fentanyl may be given as a bolus dose. The infusion rate should be titrated according to individual patient response; lower infusion rates may be sufficient.

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) alertS = Sleep, easily aroused 0 = wide awake
1 (mild) occasionally drowsy, easy to arouse1 = Awake and alert1 = easy to rouse (and can stay awake)
2 (moderate) frequently drowsy; easy to arouse 2 = Occasionally drowsy 2 = easy to rouse but unable to remain awake
3 (severe) somnolent, difficult to arouse3 = 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

Sedation of adults on a ventilator

DrugsInfusion doseConcentrationCaution
Propofol1 - 4 mg/kg/h20 mg/mlBolus dose: 1 - 3 mg/kg
Fentanyl0,5 - 2 μg/kg/h50 μg/mlHigher doses may need to be given.
Maximal dose 6 μg/kg/h
Remifentanil0,05 - 0,25 μg/kg/min50 μg/mlMay cause hyperalgesia
Dexmedetomidine0,4 - 1,4 μg/kg/h8 μg/mlStarting dose usually 0.7 μg/kg/h.
Treatment time max 2 weeks.
OBS bradycardia, hyperthermia
Clonidine0,5 - 2 μg/kg/h15 μg/ml
Midazolam0,05 - 0,2 mg/kg/h5 mg/mlBolus dose: 0,05 - 0,1 mg/kg
Morphine5 - 30 μg/kg/h1 mg/mlBolus dose: 0,05 - 0,1 mg/kg

Midazolam 1 mg/ml, 5 mg/ml iv

  • Sedative benzodiazepine. Effect within 2 min – maximal effect 5-10 min
  • Dosage:
    • Bolus adult 0.5-2 mg iv Bolus in 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)

Dexmedetomidine (Dexdor) 8 μg/ml iv

  • α1-α2 agonist 1: 1620
  • t1⁄2 = 2 h
  • Dosage: If circulatory stable give bolus 1  μg/kg in 10 min, thereafter maintenance infusion: 0.2-1.4 μg/kg/h
  • Contraindications: AV block II-III, pregnancy, pronounced hypovolemia. Combination with clonidine

Clonidine (Catapress)

  • α1-α2 1: 200 agonist, parenteral = enteral dose, t1⁄2 = 8 h – longer with continuous infusion
  • Dosage: Infusion: max 0.33 μg/kg/h alt 75-150 μg x 4. Same dose orally.
  • Contraindications: bradycardia, SSS, AV block II-III, comb with DEX, severe hypotension

Propiomazin (Propavan) tablet 25 mg

  • Dosage: 1-2 tablets no later than 20.00.
  • t1⁄2 = 8 h

Zopiclone (Imovane) 7.5 mg tablet

  • Dosage: 1 tablet by night, give before 02.00. Max 15 mg.

Haloperidol (Haldol) 5 mg/ml iv

  • Low-dose neuroleptic, dopamine blocker
  • t1⁄2 = 19 h
  • Dosage: 1-5 mg iv, 2.5-5 mg x 4 can be used experimentally. Dose reduction in liver failure
  • Caution: Parkinson’s, long QT syndrome, hypokalaemia, extrapyramidal side effects

Peptic ulcer prophylaxis

By Oskar Cavefors, Resident in anesthesia & intensive care. Sahlgrenska University Hospital.

Updated 2018-12-10


Severe gastrointestinal bleeding (GI bleeding) has been reported in scientific studies in 1.5-8.5% of intensive care patients and in some studies has been shown to be related to increased mortality 1. In studies in recent years, the risk of gastrointestinal bleeding appears to be lower, probably due to generally better intensive care or better ulcer prophylaxis 2.

Stress ulcers can occur in all critically ill patients within hours due to. severe stress, severe injury, surgery, shock or infection. The ulcerations can vary between erosive gastritis to perforated ulcer, they are usually superficial, with less capillary bleeding, but can erode into the submucosa and become more profound. Underlying vessels can be damaged and cause bleeding, or in rare cases perforation of the mucous membrane. The ulcerations are probably due to an imbalance between protective mucous mucosa and acid production in the stomach.

The mucous membrane contains glycoproteins, which provide physical protection, but also bind bicarbonate, which neutralizes the acid in the stomach. In many intensive care patients, the function of the mucous layer deteriorates due to reduced bleeding. Reflux of bile and uremic toxins can contribute to damage to the mucous membrane 3.

Acid production in the stomach is increased in head-injured patients, but probably not in other intensive care patients 4. Helicobacter pylori infection may be a contributing factor to stress ulcers 5.

Stress ulcers are most common in the fundus and corpus ventriculi, but can also occur in other parts of the gastrointestinal tract such as the duodenum and distal esophagus 6.

In a larger prospective multicenter study, a significantly increased risk of stress ulcers was seen in patients who were cared for over 48 hours in a respirator and/or had a coagulopathy, compared with other intensive care patients 7. There are also studies that point to an increased risk of other serious diseases 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 in itself has a protective effect by buffering the stomach acid, increasing mucosal blood flow and inducing secretion of cytoprotective prostaglandins and mucus 15.

However, it is uncertain whether pharmacological prophylaxis can be delayed despite ongoing enteral nutrition 16,17. A study has shown that H2 blockers in enterally nutritious patients actually lead to increased mortality 18.

Prophylaxis

To reduce the risk of developing ulcers, pharmacological prophylaxis is commonly used in intensive care patients, either given parenterally or orally. The three types of drugs mainly used for prophylaxis are proton pump inhibitors (PPIs), histamine-2 receptor blockers and sucralfate. It is not fully clear which patients will receive pharmacological prophylaxis and what effect prophylaxis has. Indications for prophylaxis and drug selection vary around Sweden and internationally. There is no scientific support for the routine administration of ulcer prophylaxis in all intensive care patients.

Recent studies have shown dubious effects of prophylaxis with PPI 19 but have also not been able to show any major damage.

Pharmacological ulcer prophylaxis is currently recommended in patients with:

  • Ventilator time over 48 hours
  • Coagulopathy (platelets <50, PT/INR > 1.5 x reference value, APT > 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, cortisone treatment (> 250 mg hydrocortisone/day)

For other patients, an individual position may be taken with regard to the patient’s risk factors.

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

Enteral nutrition is probably protective and should be initiated early, however today there is not enough knowledge to prevent ulcer prophylaxis if you belong to a risk group despite enteral nutrition.

Ulcer prophylaxis should be evaluated and terminated when the patient no longer belongs to any risk group or when intensive care ceases.

The three types of drugs used for prophylaxis are proton pump inhibitors (PPIs), histamine-2 receptor blockers and sucralfate. It seems that PPIs are more effective than H2 blockers in preventing stomach ulcers 20,21, however, there are studies that show the other way around 22. The choice of drug often depends on local routines, but it seems that proton pump inhibitors are more frequently used (in Sweden) more than other drugs. Sucralfate provides less protection against stress ulcers, but possibly also a lower risk of nosocomial pneumonia.

Risks

Ulcer prophylaxis leads to higher pH in the ventricle which enables bacterial overgrowth in the gastric mucosa. Via reflux, these bacteria reach the throat where they can then be aspirated into the airways which can result in a pneumonia, a so-called ventilator-associated pneumonia (VAP). There is a possible increased risk of VAP when treating patients with prophylaxis against stress ulcers. This risk may be greater with PPIs than sucralfate and H2-receptor blockers23.

There is also an increased risk of clostridum difficile gastroenteritis due to the increased pH in the ventricle24.

Medicines for stress ulcers

Proton pump inhibitors

These drugs are substituted benzimidazoles that reduce the secretion of hydrochloric acid by a specific blockade of the proton pumps of parietal cells. Omeprazole, esomeprazole or pantoprazole are usually given. The drugs have an equivalent effect. 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 the production of hydrochloric acid in the stomach. This inhibits the basal and stimulating secretion of hydrochloric acid in the stomach and is independent of stimulating systems such as acetylcholine, histamine and gastrin25. Omeprazole, like all antacids, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or chlorohydria. Another side effect may be hypomagnesaemia.

Omeprazole

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

Omeprazole is a weak base that is concentrated and converted to active form in the highly acidic environment of the secretory ducts of the parietal cell, where it inhibits the enzyme H+K+-ATPase – 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.

Preparation names: Omeprazol®, Losec®, Omecat®, Omestad®, Omezomyl®.

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

Dose for bleeding stomach ulcers: 40 mg x 2

Caution: Possible dose adjustment in case of severe liver failure, possible clinical interaction with clopidogrel (decreased effect), interaction with certain HIV drugs, azoles.

Esomeprazol

Proton pump inhibitor, the S-isomer of omeprazole. Available for intravenous and oral use. Completely metabolized via P450, mainly CYP2C19. Can be used during pregnancy.

Preparation name: Esomeprazole®, Nexium®, Vimovo®.

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

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

Caution: Possible dose adjustment in case of severe liver failure, possible clinical interaction with clopidogrel (decreased effect), interaction with certain HIV drugs, azoles.

Pantoprazol

Proton pump inhibitors. Available for intravenous and oral use. Virtually complete hepatic metabolism via P-450, mainly CYP2C19.

Preparation name: Pantoprazol®, Pantoloc®.

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

Caution: Possible dose adjustment in case of severe liver failure, interaction with certain HIV drugs, rifampicin and St. John’s wort.

Histamine-2 receptor blockers (H2 blockers)

H2 receptor blockers are chemically substituted aminoalkylfurans that competitively block the action of histamine on H2 receptors. This leads to reduced activation of the parietal cells and inhibits basal as well as stimulated acid secretion. However, tachyphylaxis occurs over time, with a reduced effect on the pH of the stomach. The most common preparation is ranitidine. H2-receptor blockers are excreted mainly via the kidneys, probably via active secretion.

Preparation names: Ranitidine®, Inside Brus®, Rani-Q®, Stomacid®, Zantac®, Zantac Brus®.

Standard dose: 50 mg i.v. x 3 alt. 150 mg p.o. x 2 as a tablet or oral solution.

If S-Krea > 200 μmol/l, CRRT, IHD, lower dose: 25 mg i.v. x 3 alt. 150 mg p.o. x 1.

Caution: Risk of bradycardia with rapid infusion, possibly. Dose adjustment in case of severe liver failure

Sucralfate

Sucralfate is alkaline and contains aluminum sucrose sulphate. It binds to the mucous membrane and provides a mechanical protection as well as a stimulation of factors in the mucous membrane that increase its resistance to harmful agents. Preferably given 30 minutes before food intake.

Preparation name: Andapsin®. Available as tablet Andapsin 1 g or oral suspension 200 mg/ml.

Standard dose: 1 g (5 ml) x 4

Caution: Affects the uptake of other drugs in the gastrointestinal tract, risk of constipation

References

  1. 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.
  2. 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
  3. 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.
  4. 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.
  5. Ritchie WP Jr. Role of bile acid reflux in acute hemorrhagic gastritis. World J Surg 1981; 5:189.
  6. 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.
  7. Thompson JC. Increased gastrin release following penetrating central nervous system injury. Surgery 1974; 75:720.
  8. Stremple JF, Molot, MD, Judson J. Posttraumatic gastric bleeding: Prospective gastric secretion composition. Arch Surg 1972; 105(2):177-185.
  9. Watts, CC, Clark, K. Gastric acidity in the comatose patient. J Neurosurg 1969; 30:107.
  10. 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.
  11. 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.
  12. Cook DJ. Stress ulcer prophylaxis: gastrointestinal bleeding and nosocomial pneumonia. Best evidence synthesis. Scand J Gastroenterol Suppl 1995; 210:48.
  13. Shuman RB, Schuster DP, Zuckerman GR. Prophylactic therapy for stress ulcer bleeding: a reappraisal. Ann Intern Med 1987; 106:562
  14. 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.
  15. 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.
  16. McBride DQ, Rodts GE. Intensive care of patients with spinal trauma. Neurosurg Clin N Am 1994; 5:755.
  17. 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.
  18. 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.
  19. Guillamondegui, OD, Gunter OL, et al. Practice management guidelines for stress ulcer prophylaxis, Eastern Association for the Surgery of Trauma (EAST) (Published 2008).
  20. Pingleton SK, Hadzima SK. Enteral alimentation and gastrointestinal bleeding in mechanically ventilated patients. Crit Care Med 1983 Jan;11(1):13-6.
  21. 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.
  22. 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?
  23. 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.
  24. 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.
  25. 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.
  26. 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.
  27. 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
  28. 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.
  29. Rang & Dale’s Pharmacology – 8th Edition – Elsevier (??)
  30. 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.

Sepsis – Septic shock

Modified from a Swedish local Treatment Protocol [Region Skåne] for Severe Sepsis. Note that deviations may exist in different countries, check your own hospital’s local program and best-before date.

Updated 2020-09-26


Background

Early identification and correct treatment of patients with severe sepsis (“Blood poisoning”) will reduce mortality. Severe sepsis can affect everyone, but infants and elderly are at increased risk, as well as people with chronic diseases or impaired immune systems. Safe prevalence data is missing in Sweden but probably affects 100-300 people per 100,000 inhabitants and years. Mortality has been very high in previous studies, severe sepsis 20% and septic shock 45%. Later studies show a mortality rate of around 15-20%. Severe sepsis is one of the conditions for an emergency situation which is associated with highest mortality. According to international and national recommendations, patients with severe sepsis should receive proper antibiotic treatment within one hour of arrival at the hospital. Research has shown that early treatment with antibiotics, intravenous fluid, oxygen and supportive therapy is vital in severe sepsis. Inadequate initial antibiotic therapy in severe sepsis with positive blood culture leads to a doubling of mortality. Delayed adequate antibiotic treatment at septic shock increases mortality by almost 8 percent per hour during the first 6 hours. The more organ systems fail and the higher the initial lactate level, the higher the mortality. This treatment protocol describes a sepsis drug for the emergency treatment of patients who have or suspected to be suffering from severe sepsis and septic shock. The goal of the sepsis chain is to identify patients with an infection at risk of developing severe sepsis early on. As part of the sepsis chain, we have prepared support for treatment prehospitally, at the emergency room and in the correct care area. The chain of care is supported by cooperation between several different areas of health care and focuses on early identification and treatment without delay.

Sequential Organ Failure Assessment (SOFA) Score

Organ System
Score
01234
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<2020–3233–101102–204>204
Circulation
Blood Pressure/CatecholaminesMean arterial pressure ≥70 mm HgMean arterial pressure <70 mm HgDopamine <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 1513–14 10–126–9<6
Reaction Level Scale1234–56–8
Renal Function
Creatinine, μmol/l and/or diuresis, ml/day<110110–170171–299300–440
<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.

Definition of Sepsis

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

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

New definitions, diagnostic criteria and codes for sepsis and septic shock according to Sepsis-3

 Sepsis Septic Chock
Definition Life-threatening organ dysfunction caused by systemic response to infectionA subset of sepsis where underlying circulatory and cellular / metabolic disorders are sufficiently pronounced to significantly increase mortality
Diagnostic CriteriaAcute change infection corresponding to at least 2 SOFA points 1Remaining 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 2R57.2 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 meet the patient’s criteria for sepsis, however, what we in everyday terms call “sepsis or septic” is in fact, severe sepsis or septic shock, that is, the infection has led to hypotension, hypoperfusion and/or organ failure. The Swedish Infectious Disease Association has developed guidelines for assessing severe sepsis and septic shock as described below. The changes should be caused by a systemic reaction and not be a direct effect of local infection focus, the changes should be newcomers and not caused by other underlying disease. For the definition of severe sepsis to be met, the patient must have sepsis as described above and that one or more of the following criteria are present;

Hypotension

  • Systolic blood pressure < 90 mm Hg

Organ dysfunction

  • Changed mental status;
    • Confusion
    • Anxiety
    • Aggressiveness
    • Somnolence
  • Renal failure;
    • S-Creatinine increase > 45 μmol/L or
    • Oliguria, urinary output < 0.5 ml/kg for at least 2 hours despite adequate fluid supply
  • Respiratory insufficiency:
    • pO2 < 7.0 kPa on air (SaO2 approximately < 86%)
    • pO2 < 5.6 kPa on air (approximately < 78%) if the lung is the focus of the infection
  • Coagulopathy;
    • Petechiaes
    • Echymoses
    • INR > 1.5
    • APT time > 60 sec
    • Platelets < 100
  • Liver affection;
    • s-Bilirubin > 45 μmol/L

Hypoperfusion

  • Lactate > 1 mmol above the upper reference value, all BE ≤ 5 mmol/L
  • Reduced capillary refill
  • Cold moist skin
  • Skin marmoration, discolorization

*Bowel problems (lack of bowel noise/gastrointestinal disorders such as abdominal pain, diarrhea or vomiting) are assessed as organ effects in international guidelines, but not in the Swedish Infectious Diseases Doctors’ guidelines.

The many times fast and hard-to-predict disease progression in severe sepsis emphasizes the importance of clear routines for monitoring vital parameters and set limits for doctor contact and intensive care. Especially during the first day after sepsis debut, patients are at risk of deterioration, which justifies increased monitoring and preparedness during this period to prevent development to;

  • Progressive severe sepsis: impairment of vital parameters or rising lactate during observation time.
  • Septic shock: sepsis with hypotension despite adequate fluid therapy.

Epidemiology

Severe sepsis can affect everyone, but infants and elderly are at increased risk, as well as people with chronic diseases or impaired immune systems. Safe prevalence data is missing in Sweden but sepsis probably affects 100-300 people per 100,000 per inhabitant and year.

Preventive Measures

Appropriate treatment of antibiotic-requiring infections without unnecessary delay is important to prevent the development of severe sepsis. Work with National Guidelines for antibiotic therapy (In Sweden called “STRAMA – Guidelines“) is a good application for physicians to provide antibiotics with the correct indication. An overly wide range of antibiotics may risk creating conditions for the development of antibiotic resistance, which in turn may adversely affect the result of severe sepsis. For more information about STRAMA’s Outpatient Guidelines – here is a link.

General vaccination programs are essential for preventing the development of certain serious infectious diseases. Annual influenza vaccination of risk groups may be particularly noted as an important measure for preventing secondary sepsis cases, as well as pneumococcal vaccination according to given recommendations. Immune-suppressed patients constitute a particularly exposed group and it is therefore of great importance that these patients in infectious complications meet physicians with the appropriate skills to assess the sometimes diffuse symptoms that may occur or indicate a serious infection. It is also important to inform patients with immuno suppressive treatment how to act at signs of infection. Occasionally, special vaccination may be indicated in immuno suppression.

Symptoms, Clinical Findings and Early Identification

Severe sepsis is a serious infection that is characterized by organ damage. Most patients with acquired severe sepsis and septic shock are classified as red or orange alarms according to the Rapid Emergency Triage and Treatment System (RETTS) already on arrival at the emergency ward. However, the initial clinical picture may be difficult to interpret and a range of symptoms and clinical findings may occur which may vary depending on the source of the infection, infectious agent and patient age and comorbidity.

Patients with severe sepsis or septic shock often have fever or a history of fever and one of the following; tachycardia > 90/min, increased respiratory rate > 20/min, drop in blood pressure, low oxygen saturation < 90 %, anxiety and confusion, gastrointestinal symptoms such as abdominal pain, diarrhea or vomiting. With typical symptoms and an acute illness with chills, high fever and affected general condition, it is easy to suspect severe sepsis, but many patients, especially elderly people, often exhibit a more atypical picture with confusion as the only presenting symptom of severe sepsis. It is important to always have sepsis in mind when investigating a severely ill patient with an unclear diagnosis.

Please note the following symptoms of a severe infection:

C-BRS – Consciousness/Blood Pressure/Respiratory Rate/Oxygen Saturation, or the 90/30/90 rule:

  • Consciousness; reduced/impaired mental status
  • Systolic blood pressure < 90 mm Hg
  • Respiratory rate > 30 breaths per minute
  • Saturation < 90%

Sepsis Alarm

To allow early identification, a sepsis alarm should be used, which means a modified version of RETTS for focus on patients at risk of serious infection. Rapid Emergency Triage and Treatment System (RETTS) is the sorting system used for many emergency services around the world. RETTS is based on registration of vital parameters (blood pressure, heart rate, respiratory rate, vomiting and temperature) with specified limits to sort patients to the correct priority group.

Red Alarm by RETTS means that the patient’s oxygenation is below 90% despite oxygen treatment, the respiratory rate is over 30 or below 8, blood pressure < 90 mm Hg, pulse rate > 130 or the patient develop convulsions or is unconscious.

To vital parameters, a so-called “ESS” (Emergency Signs and Symptoms) is added. In severe sepsis, ESS 47 may be added (infection, fever, local infection). ESS 51 should also be added (known as adrenal, corticosteroid, immunodeficiency or immunosuppression) which ultimately determines the patient’s priority.

Sepsis alarm is called out in patients with red RETTS who have fever or a medical history of fever. In these cases, the patient is triaged according to a special algorithm and the physician/emergency doctor is called to the emergency room immediately when the patient arrives.

By early focus on patients who have established sepsis or is at risk of severe sepsis, it is ensured that the patient receives adequate antibiotics within 60 minutes after sampling of blood cultures (2 + 2) and proper supportive treatment is initiated and continued with i.v. fluid and oxygen.

CHECK POINTS TO BE CONSIDERED TO RECOGNIZE PATIENTS WITH SEVERE SEPSIS

  • Fever (> 38.0 °C) does not always occur and ear thermometers are unreliable. Low body temperature (< 36.0 °C) can be a serious sign of severe sepsis
  • “Patient found on the floor” may be secondary to sepsis
  • Sepsis-triggered confusion can be misinterpreted as stroke
  • Keep in mind that gastrointestinal symptoms and flu-like conditions may be due to severe sepsis
  • CRP can be normal or only moderately elevated initially
  • Note colour of the skin – subcutaneous bleedings? Infected wounds? Petechial spots?
  • Observe reduced immune responses in certain groups, e g patients with rheumatic systemic diseases, IBD, malignant tumor diseases, transplanted patients, splenectomized patients, and patients with ongoing or recent treatment with immunomodulatory drugs (such as corticosteroids, Prednisolon® 15 mg or more, Metothrexate®, Remicade® (Infliximab) or Enbrel® (Etanercept))

Primary Target

  • Adequate monitoring – follow blood pressure, pulse, oxygen saturation, consciousness!
  • Establish peripheral vascular access (x 2)
  • Oxygen 2-5 liters by nasal cannula, > 5 liters by mask, oxygen saturation > 93 %. Caution in COPD! Inform the emergency ward if the patient has COPD.
  • Infusion of crystalloid solutions; Ringer’s Acetate, if SBP < 90 mm Hg, a bolus dose is administered of 500-1 000 ml for 30 minutes, repeat to treatment target, i.e. SBP > 90 mm Hg. In total, at least 30 ml/kg of crystallloids i.v. should be given within 3 hours of severe sepsis with hypotension.
  • Paracetamol is given only when the patient is clinically affected by fever or in ongoing cerebral ischemia/convulsions/cardiac ischemia.

 Prehospital Identification and Treatment

  • Suspicious infection is generally identified using the RETTS classification
  • ESS 47 is added to vital parameters, which determines the patient’s priority.
  • In some cases, ESS 51 (known adrenal corticosteroid deficiency, immuno deficiency or immuno suppression) should also be used.
  • In addition to this analysis, one should also note the following criteria that are indicative of suspected severe infection;
  • Fever (temp > 38.0 °C) or low temp (< 36.0 °C) and any of the following symptoms/signs:
    • Petechiaes/rash
    • Signs of infected skin/soft parts/joints
    • New severe pain
    • Cerebral affection/severe headache
    • Urinary tract symptoms (especially in patients with urinary catheter)
    • CVC or other vascular port with signs of infection

Epidemiology? Always ask the patients if they have been traveling abroad lately

Keep in mind that fever may be absent in immunosuppressed patients and in patients taking paracetamol and NSAID:s, and diarrhea/abdominal pain/vomiting are common symptoms in severe sepsis.

  • Oxygen 2-5 liters by nasal cannula or > 5 liters by mask, to reach an oxygen saturation > 93 %. Caution in COPD! Inform the emergency ward if the patient has COPD.
  • Establish peripheral vascular access (x 2)
  • Consider an intraosseos vascular access when difficulties with PVC in critically ill patients who are immediately in need of fluid/drug administration.
  • Infusion of crystalloids such as Ringer’s solution. If SBP < 90 mm Hg give a bolus dose of 500-1 000 ml for 30 min, repeat to achieve treatment goal, i.e. SBP > 90 mm Hg. In total, at least 30 ml/kg i.v. should be given within 3 hours in case of severe sepsis with hypotension.
  • Disallow general paracetamol ordination when the indication is fever. Pharmacological reduction of fever is given only when the patient is clinically affected by the fever or in ongoing cerebral ischemia/convulsion/cardiac ischemia.

In Hospital Diagnostics and Treatment

Primary Clinical Investigation

  • Initial emergency care according to A – B – C – D – E
  • Peripheral vascular access (PVC x 2)
  • Consider a central venous line or intraosseous access if difficulty of PVC in critically ill patients who are immediately in need of access to fluid/drug administration.
  • Blood culture (2 + 2)
  • Blood gas sampling, arterial or venous for the analysis of lactate
  • Blood samples; CRP, leukocytes, thrombocytes, PK/INR, APT time, liver transaminases, urinary-stick, B-glucose.
  • Urine cultivation (if necessary by urinary catheter) and other relevant cultures after prescription.
  • Is there a suspected bacterial infection? Determine infectious focus. After adequate cultivation, determine relevant choice of antibiotics
  • If meningitis is suspected consider lumbal puncture, see National Guidelines [In Sweden: www.infektion.net]
  • ECG
  • Consider x-ray thorax/pulmonary bedside and other radiological examinations
  • Check vital parameters every 5 minutes initially until the patient is stabilized
  • Epidemiology? Always ask the patient if they have been traveling abroad
  • Keep in mind that fever may be lacking in immunosuppressed patients and in patients taking paracetamol and NSAIDs, and diarrhea/abdominal pain/vomiting are common symptoms in severe sepsis.

Treatment

  • Infectious Disease Consultants/Emergency Medicine Physicians should be present in the emergency department during a sepsis alert. If infectious disease specialists are not available in the hospital, they should be contacted by telephone for advice on primary care and choice of antibiotics, especially in immunosuppressed patients and those patients who may carry resistant bacteria.
  • Give oxygen 2-5 liters by nasal cannula, or > 5 liters by mask to reach an oxygen saturation > 93 %. Caution in patients with COPD! Inform the emergency ward if the patient has COPD.
  • Infusion of crystalloids such as Ringer’s acetate. If SBP < 90 mm Hg give a bolus dose of 500-1 000 ml for 30 min, repeat to target SBP > 90 mm Hg. In total, at least 30 ml/kg i.v. should be given within 3 hours in case of severe sepsis with hypotension or lactate > 4
  • Choice of antibiotics is based on the severity of the infection and possibly, suspicious focus.

If antibiotics are prescribed, they should be given without delay at the emergency department!

  • Consider invasive treatment of infection focus (e.g. Source Control) at e.g. septic arthritis, abscess, pyelitis, empyema, intestinal perforation, gynecological infection or necrotizing fasciitis. Consult relevant surgeon.
  • If the patient is on or recently discontinued treatment with cortisone, give Solu-Cortef 100 mg i.v.
  • Urinary catheter with urinary output, target level 0.5 ml/kg/h.
  • Give Albumin 20% 100 ml for continued hypotension after 2-3 liters of crystalloids (Ringer Acetate), do not use starch preparations (e g Voluven, HAES), if Albumin is not available, continue with Ringer Acetate.
  • Refrain from generalized paracetamol prescription in presence of fever. Paracetamol is given only when the patient is clinically affected by the fever or in ongoing cerebral ischemia/convulsion/cardiac ischemia. Paracetamol should be avoided in cases of liver affection.

* Which specialists who are consulted is adapted to the respective hospitals capacity; in hospitals where infectious disease specialists are available, these should be consulted, otherwise medical or emergency medical services according to local guidelines.

Level of Care – Admission of Patient

  • Decision on appropriate level of care; Intensive Care Unit/Intermediary Care or regular ward.
  • Consider need for isolation in case of resistant strains (ESBL, MRSA)
  • Transfer to an infectious disease ward, emergency ward or other ward with sufficient monitoring resources without delay, during waiting time to ward, vital parameters must be checked every 15 minutes.
  • Evaluate if there are evidence for treatment limitations

Emergency Ward – Progressive Decline of Vital Parameters after Initial Action

Establish contact with MIG-teams or ICU physician (or Infectious Consultant) for immediate referral to ICU care:

  • If SBP < 90 mm Hg despite i.v. fluid or
  • Oxygen saturation <90 despite oxygen
  • If lactate > 4 or ascending
  • If RR > 30 despite treatment
  • In case of serious organ failure, such as consciousness reduction

Clinical Investigation

  • Peripheral vascular access (x 2)
  • Consider a central venous line or intraosseous access if difficulty of PVC in critically ill patients who are immediately in need of access to fluid/drug administration.
  • Blood cultures (2 + 2)
  • Blood gas analysis, arterial or venous for the analysis of lactate
  • Relevant blood samples; CRP, leukocytes, thrombocytes, PK/INR, APT time, liver status, u-screen check, B-glucose.
  • Urine cultivation (if necessary by urinary catheter) and other relevant cultures after ordination.
  • Is there a suspected bacterial infection? Determine infection origen. After adequate cultivation, determine relevant choice of antibiotics
  • If meningitis is suspected consider lumbal puncture, see National Guidelines [In Sweden: www.infektion.net]
  • ECG
  • Consider radiological examinations such as x-ray thorax/lungs bedside
  • Check vital parameters every 5 minutes initially until the patient is stabilized.
  • Epidemiology? Always ask the patient if they have been traveling abroad
  • Keep in mind that fever may be lacking in immunosuppressed patients and in patients taking paracetamol and NSAIDs, and diarrhea/abdominal pain/vomiting are common symptoms in severe sepsis.

Treatment

  • Daytime preferentially treatment by infectious disease specialist*, on-call consultation or by telephone, assess the patient in the emergency ward, especially in immunosuppressed patients and in patients with known support of resistant bacteria.
  • Give oxygen, targeted by oxygen saturation, 1-5 liters on nasal cannula, or > 5 liters by mask, treatment aims at oxygen saturation > 93%. Caution in COPD!
    Infusion of crystalloid solutions (Ringer Acetate) 1 000 ml, in total, at least 30 ml/kg i.v. given within 3 hours of severe sepsis with hypotension or lactate > 4
  • Choice of antibiotics is based on the severity of the infection and possibly, suspicious focus.

If antibiotics are prescribed, they should be given without delay at the emergency department!

  • Consider invasive action of infection focus (e g source control) at e.g. septic arthritis, abscess, pyelitis, empyema, intestinal perforation, gynecological infection or necrotizing fasciitis.
  • If the patient is on or recently discontinued treatment with cortisone, give Solucortef 100 mg i.v.
  • Antipyretic agents is given only when the patient is clinically affected by fever or in an ongoing cerebral ischemia/convulsion/cardiac ischemia. Refrain from general ordination of paracetamol when the indication is fever.

* Which specialists who are consulted should be adapted to each hospitals capacity; in hospitals where infectious disease specialists are available, these should be consulted, otherwise medical or emergency medical services according to local guidelines.


Lung fibrosis / Bronchiolitis / Interstitial pneumonia

Idiopathic interstitial pneumonia (IIP)

Is a group of several interstitial lung diseases.

IPF – Idiopathic pulmonary fibrosis

Previously, the diagnosis IFA (Idiopathic Fibrotating Alveolitis) has also been used. IPF is morphologically equivalent to UIP (“usual interstitial pneumonia”). Common symptoms are shortness of breath, fatigue and cough.

UIP/NSIP (Usual Interstitial Pneumonia – UIP)

The etiology is unknown. The disease responds poorly to treatment and has a poor prognosis. These patients usually need to be transplanted, both lungs being replaced. Lung transplantation has a 5-year mortality of about 70-75%.

  • UIP is also called cryptogenic fibrotizing alveolitis
  • Histological pattern is called common interstitial pneumonia
  • In order for the diagnosis of Idiopathic pulmonary fibrosis to be made, a specific histological pattern must be demonstrated, while other known causes of the pathology are excluded.
  • Other known causes of the pattern formation: asbestosis, collagen vascular diseases, etc.
  • Men are more commonly affected than women
  • Two thirds of patients are older than 60.
  • Leads to severe hypoxemia and cyanosis.

Morphology at UIP

  • One sees a specific histological pattern called interstitial pneumonia (UIP)
  • Macroscopically, the surface of the lung resembles cobblestones due to. scars in interlobular septa contracted.
  • The cut surface shows fibrosis (solid rubber-like white surfaces)
  • The lower lobes dominate the fibrosis
  • Microscopically, spotted interstitial fibrosis is seen, which varies in intensity and over time. A lot of fibroblasts occur initially, then more collagenous wounds that are not as cellular. The walls of the alveoli collapse. Cysts are formed that are lined with type-2 pneumocytes or bronchiolar epithelium (“honeycomb pattern”). The pulmonary arteries often change as a result of pulmonary hypertension with hyperplasia, intimate and media thickening.

Clinical picture

  • Insidious disease course with gradual deterioration of lung function. The patient develops unproductive cough and gradually more shortness of breath.
  • Dry or “velcro-like” inspirational rattles are common
  • Cyanosis, cor pulmonale, peripheral edema may occur later

Nonspecific interstitial pneumonia (NSIP – nonspecific interstitial pneumonia)

Dyspnoea and cough for several months are the most common symptoms. The diagnosis NSIP can be established when the patient has pneumonia with interstitial changes without another diagnosis either cellular or fibrous histopathological pattern. The cellular pattern means a better prognosis for the patient than the fibrous one.

  • NSIP shows a different histopathological pattern than that of idiopathic pulmonary fibrosis
  • NSIP has a better prognosis than idiopathic pulmonary fibrosis, so the diagnosis is important to make.

Morphology

  • Cellular changes with mild to moderate chronic interstitial inflammation with lymphocytes and some plasma cells. You can see a uniform or spotted pattern.
  • Histopathologically, the fibrous changes are seen to have diffuse or patchy interstitial distribution in which all scars are equally obsolete (unlike the idiopathic pulmonary fibrosis which has the appearance of scars of different ages).
  • Fibroblast foci are usually absent.

BOOP, COP (Bronchiolitis Obliterans – Organizing Pneumonia)

Responds better to treatment. Treatment is given with steroids, cortisone. BOOP has a relatively good forecast.

Cryptogenic Organizing Pneumonia (COP / BOOP)

  • Also known as Bronchiolitis Obliterans Organizing Pneumonia (BOOP)
  • Cryptogen = unknown etiology
  • You see patchy consolidation (densification) of the airways. The infiltrates look the same as in a pneumonia, but have the peculiarity that they move with time. The symptoms are also the same.
  • The disease is often diagnosed in an infection ward where a patient with pneumonia does not respond to antibiotics.
  • Then a new lung X-ray is taken and you can see that the infiltrate has moved. Treatment is usually given with cortisone and the patient improves.
  • Polyparate plugs of loose connective tissue form in alveolar ducts, alveoli and bronchioles
  • The connective tissue is the same age everywhere
  • The lung architecture is intact
  • Some patients recover spontaneously, but most require treatment with oral steroids for 6 months or more.
  • This disease can also occur as a complication of infections or inflammatory damage to the lungs.

Pneumoconiosis

  • Non-cancerous diseases that occur due to inhalation of mineral dust, organic and inorganic particles as well as chemical fumes and vapors.
  • The most common mineral-induced pneumoconiosis is the result of inhalation of carbon dust, silica and asbestos.
  • These diseases are almost always work-related and were more common in the past.

Pathogenesis

  • The particles are most harmful if they get stuck in the bifurcations in the distal airways.
  • > 500 μm particles are too large to get out
  • < 0.5 μm large particles tend to act as gases and move in and out of the alveoli without depositing and causing any particular damage.
  • 15 μm particles are the most dangerous.
  • Carbon is quite inactive and large amounts must be deposited in the lungs to cause damage.
  • Silica, asbestos and beryllium are more reactive and lead to fibrous reactions at lower concentrations.
  • Most particles get stuck in the cilia and are brought up again by mucous mucus.
  • Some, however, get caught up in bifurcations and attract macrophages that endocyte them.
  • The more reactive particles then trigger the macrophages to release substances that initiate an inflammatory response with fibroblast proliferation and collagen deposition.
  • Some particles can reach the lymph nodes via drainage or inside migrating macrophages and thus initiate an immune response against components on the particles or their own proteins that have been modified by the particles.
  • Leads to strengthening and widening of the local reaction.
  • Tobacco smoking exacerbates the effects of all inhaled mineral dust. This is especially true for asbestos.

Coal worker pneumoconiosis

  • Occurs (mainly in the past) in coal workers due to the coal dust they breathe in during mining
  • Affects different patients differently: asymptomatic anthrax (cold dust lung): Pigment accumulation without visible cellular reaction.
  • Simple charcoal worker pneumoconiosis: accumulation of macrophages with little or no pulmonary dysfunction.
  • Complicated charcoal worker pneumoconiosis: Fibrosis is extensive and lung function is affected
  • The patient develops progressive massive fibrosis (PMF)
  • Wide range of clinical effects: from asymptomatic pigmentation to mild dysfunction to pulmonary dysfunction, pulmonary hypertension and cor pulmonale.
  • Fibrosis (PMF) tends to worsen without inhaling more carbon.
  • Coal mining dust contains a number of trace metals that can increase the harmful effects of coal in the dust.
  • No increased risk of bronchogenic carcinoma in coal workers compared to the standard population if smoking is taken into account as a risk factor. This distinguishes the carbon exposure from the silica and asbestos.

Silicosis

  • Most prevalent chronic occupational injury in the world.
  • Inhalation of crystalline silica: In the form of i.a. quartz, cristobalite, tridymite (quartz most common cause of silicosis of these)
  • Pathogenesis: the silicon particles are eaten by macrophages and activate them due to its reactivity. The macrophages release IL1, TNF, fibronectin, lipid mediators [PG, TX?], Free radicals, fibrogenic cytokines [PDGF, TGFβ?]
  • Silicon has a less toxic effect when mixed with other metals.
  • Miners who mine hematite ore may have more silicon in their lungs than some sick quartz-exposed workers, but still have a relatively mild disease due to. that the iron in the ore has a protective effect.
  • Silicosis is usually detected during routine X-ray examinations of asymptomatic workers exposed to silica fume.
  • Fine nodules are found in the upper lungs, but the effect on lung function is usually small or non-existent.
  • Symptoms appear later when the disease progresses to PMF. Then patients get pulmonary hypertension, cor pulmonale.
  • It takes a long time before you die of the disease, but the ability to work can be greatly reduced due to reduced lung function.
  • Silicon exposure increases the risk of tuberculosis, probably due to repression of cell-mediated immune systems and making it more difficult for macrophages to destroy phagocytic bacteria as a result of the silicon crystals they have eaten.
  • Silica crystals are carcinogenic.

Asbestosis

  • Asbestos exposure causes parenchymal interstitial fibrosis (asbestosis), localized fibrous plaques or diffuse fibrosis in the pleura, pleural effusions (fluid in the pleura), bronchogenic carcinoma, laryngeal carcinoma, malignant pleural and peritoneal mesothelioma.
  • Whether or not the exposure makes the person ill is determined by the concentration, size, shape and solubility of the asbestos.
  • Serpentine asbestos is curly and flexible. It sticks more easily to the mucus of the upper respiratory tract and is transported out of the lungs. It is also more water-soluble and thus leaches out of the lung tissue if it is stuck further down.
  • Amphibole asbestos is the fiber straight, stiff and brittle. It is mostly pathogenic. The amphibole asbestos particles lie straight in the air stream and thus pass further down into the airways. They can penetrate the airway epithelium down there and enter the underlying connective tissue.
  • However, both forms can produce asbestosis and cancer.
  • Asbestos causes fibrosis by interacting with lung macrophages.
  • Asbestosis causes progressively worsening dyspnoea that occurs 1020 years after asbestos exposure. Usually patients also get productive cough (sputum is coughed up)
  • The disease can remain static or progress to heart failure, cor pulmonale and death.
  • Patients have a 5-fold increased risk of developing bronchogenic carcinoma.
  • Cigarette smoking in connection with asbestos exposure greatly increases the risk of developing this cancer, smoking + asbestos = 50 times increased risk of bronchial carcinoma.
  • The risk of malignant mesothelioma is 1000-fold increased (this cancer is very rare, 217 cases per 1,000,000 ordinary people).
  • Pleural plaque: White plaques that sit on visceral / parietal pleura at hilus height. Can also sit on the diaphragm. If they contain calcium, they are pathognomonic for asbestosis.

Drug-induced and radiation-induced lung disease

  • Both acute and chronic injuries to the lungs.
  • Bleomycin, a cancer drug, can cause pneumonitis and interstitial fibrosis due to direct toxicity of the drug and through the migration of inflammatory cells to the alveoli.
  • Amiodarone (Cordarone), an antiarrhythmic drug, can also cause interstitial fibrosis and pneumonitis.
  • Radiation therapy for lung cancer causes acute pneumonitis after 16 months in 20% of all treated patients. Causes fever and dyspnoea disproportionate to the amount of lung irradiated. May heal with corticosteroid therapy or turn into chronic radiation pneumonitis.

Granulomatous diseases

Sarcoidosis

  • The most common idiopathic interstitial lung disease.
  • Sarcoidosis is a multisystem disease with an unknown etiology.
  • Characterized by non-caseous granuloma formation in many organs and tissues. In the lungs, granuloma formation occurs in the parenchyma and in the mediastinal glands.
  • Mycobacterial and fungal infections can also cause these granulomas, so the sarcoidosis diagnosis is made only when they have been ruled out.
  • Involvement of the lungs in many cases gives the main symptoms that cause the disease to be detected.

Symptomatology

  • Acute: The acute sarcoidosis typically presents with bilateral angry arthritic arthritis, more often in women. The patient has a fever, low/no CRP and has a history of cough for a while.
  • Chronic: Uveitis/iritis. Prolonged cough.
  • Skin rash: Seen on skin involvement. Reddened rashes that tend to settle in old scars (after operations, for example), which then change shape. Biopsy shows granuloma. Erythema nodosum (tuberose).
  • Very varied course.
  • Completely asymptomatic in many individuals.
  • 2/3 of those who get symptoms get respiratory symptoms.
  • Shortness of breath, dry cough, vaguely substantial discomfort

Diagnostics

  • Pulmonary X-ray: Shows bilateral hilus lymphoma. Unilateral lymphoma indicates TB / lymphoma / lung cancer.
  • Diagnosis is made when the non-caseous granulomas are found in a biopsy and all other known causes for their origin have been ruled out.
  • Serum ACE: Indicates disease activity.

Treatment

  • Corticosteroids: 40 mg prednisolone in a phase-out schedule.
  • Methotrexate: The absolute indication for treatment is: Sarcoidosis + uveitis

Prognosis

  • 60-75% of affected individuals recover with minimal or no remaining damage. Those with acute onset disease have a better prognosis.
  • 20% get permanent lung dysfunction or visual impairment. The disease can also affect other organs (CNS, heart)
  • 10-15% succumb to progressive pulmonary fibrosis and cor pulmonale.

Allergic alveolitis (hypersensitivity pneumonia)

  • Called allergic alveolitis as it affects the alveoli unlike asthma which mainly affects the bronchi.
  • Immunologically mediated inflammatory disease: A mixture of type III (immune complex) and type IV (cell mediated) hypersensitivity.
  • Most commonly resulting from increased sensitivity to stale hay or other antigens inhaled in the workplace (agriculture).
  • The triggers are very different, but the syndromes that occur have similar clinical and pathological findings and probably very similar pathophysiology.
  • Examples of agents: Bacteria, fungi, animal proteins (pigeon, budgerigar, rats, pigs, cows), chemicals
  • Names after triggering agent: “Farmer’s lung, Birdfencer’s lung, Sawmill lung”.
  • Provides restrictive lung disease with reduced diffusion capacity, compliance and total lung volume.

Morphology

  • Mottled mononuclear infiltrates of the lung interstitium
  • Interstitial non-caseous granulomas (as in sarcoidosis) are seen in 2/3 of cases.
  • In advanced chronic cases, diffuse interstitial fibrosis occurs.

Symptoms

  • Acute reaction 48 hours after exposure to the antigen: fever (39 degrees), dry cough, dyspnoea, myalgia, arthralgia
    If the exposure to the antigen disappears after the acute attack, the disease heals completely.
  • Chronic disease: If the antigen is not removed from the environment, the patient eventually develops chronic interstitial lung disease (diffuse interstitial changes in the lungs) but the acute more severe episodes after exposure.
  • Insidious chronic illness with productive cough, dyspnoea, fatigue, nausea and weight loss.

Diagnostics

  • Rattle and ronki and possibly. cyanosis in acute form.
  • Precipitating antibodies to mold panel.

Treatment

  • Cortisone in tapering in acute illness.
  • Remove the agent! If this is done, lung function can be completely restored. If there has been fibrosis, however, the disability is permanent. Eliminating an agent can in many cases mean a major life change. A farmer may have to stop working on his farm, for example.

Neurointensive care in subarachnoid hemorrhage (SAH)

By Helena Hergés Odenstedt, Chief Physician, in Anesthesia & Intensive Care, Sahlgrenska University Hospital.

Updated 2020-12-28


Subarachnoid hemorrhage (SAH)

Background

  • Incidence 10 per 100,000 inhabitants/year
  • At a university clinic in Gothenburg (approx 1 mill inhabitants), about 100 patients are cared for with SAB per year
  • Intensive care period is often 7-10 days
  • Slightly more women than men receive SAH
  • The median age of onset is 50-60 years

Clinical picture

  • Sudden onset of intense headache, “thunder headache”
  • Nausea
  • Neck stiffness
  • Photosensitivity
  • Loss of consciousness

CT-scan (bleeding is usually clearly visible)

When the aneurysm ruptures, blood enters the subarachnoid space (SA space) which means ICP rises and CPP drops, which can cause thunder headaches, loss of consciousness and global cerebral ischemia. The blood redistributes and the ICP decreases in those who wake up. In addition, blood in the SA compartment can cause outflow obstruction for cerebrospinal fluid, which results in hydrocephalus, which in turn increases ICP. Furthermore, there is an activation of inflammation, platelets, the coagulation system as well as endothelial damage and excitotoxic effect of blood with its degradation products.

Sometimes lumbar puncture

  • Warning bleeding!?

CT image

Clinical development

  • Aneurysm rupture – in 80% of cases
  • Blood into the subarachnoid space (not infrequently also in the ventricular system and the brain parenchyma)
  • Increased ICP leads to severe instant headache
  • Decreased CPP (cerebral perfusion pressure) gives ev. loss of consciousness / global ischemia
  • Redistribution of blood
  • ICP drops leads to usually improved consciousness

Blood with degradation products in the subarachnoid space also gives

  • Drainage obstruction for cerebrospinal fluid which can result in hydrocephalus
  • CSF  production is about 500 ml/day
  • May cause ICP increase early after bleeding

Treatment goals at SAH

  • Prevent rebleeding
  • Treat the aneurysm
  • Counteract and treat any complications such as
    • Hydrocephalus
    • Vasospasm
    • Ischemia
    • Epilepsy
    • Intensive care-related complications
  • Optimize the conditions for recovery

Initial care

  • Ensure vital functions and prevent rebleeding
  • 30% risk of rebleeding in the first week of untreated aneurysm
  • SBP < 160 mm Hg (systolic blood pressure)
  • Tranexamic acid 1-2 g i v
  • Calm and stress-free environment
  • Analgesics
  • Antiemetics
  • Monitoring
  • Nimodipine (Nimotop) infusion

Initial clinical picture varies

If GCS grade 1

  • Taken to the neurosurgical care department /neuro intensive care for monitoring and investigation
  • CT angio and possibly conventional angiography with endovascular procedure alt. open neurosurgical surgery

Gradually declining consciousness

  • Taken to the neurosurgical ward/neuro intensive care for supervision
  • Intubate if GCS < 9 (RLS > 3)
  • Possible hydrocephalus with need for ventricular drainage (V-drain) before further investigation and aneurysm treatment

Deeply unconscious patient

  • Sometimes left at first clinic to wait for ev. improvement before transfer to neurosurgical department
  • Often with hydrocephalus and getting V-drains before deciding on aneurysm treatment

Radiological investigation of the source of bleeding

If no source of bleeding is found, angiography is usually performed again after 1 week

CT Angiography

Treatment of the aneurysm

  • Endovascular coiling
  • Surgical clipping
  • Flow diversion

Intensive care after the aneurysm is secured

Clinical neurological monitoring

  • Preferably unsedated patient who is easy to evaluate on repeated occasions
  • Note hydrocephalus development
  • Vasospasm development

May need inotropic support and respiratory needs that require sedation

  • Inflammatory activation
  • Stress induced cardiomyopathy/neurogenic pulmonary edema
  • Impaired consciousness
  • Give no more than comfort sedation to facilitate neurological evaluation

Hydrocephalus (HC)

  • Due to cerebrospinal fluid resorption disorder
  • Normally about 500 ml/day is formed
  • Slow decrease in consciousness (hours)
  • Sunset view of the eyes
  • Treatment: ventricular – drain
  • Set the V drain to a level above which CSF is drained. ICP does not exceed the set level
  • May come urgently or later in the process
  • If the drain cannot be closed, the shunt becomes relevant

“Vasospasm” – a dreaded complication

  • DCI – Delayed cerebral ischemia
  • Includes everything from transient neurological symptoms to manifest infarctions
  • Greatest significance for the outcome of those who survived initially
  • Usually develops between days 3-14 and affects 30% of patients
  • The worse the patient, the greater the risk of vasospasm
  • May have to do with proinflammatory environment
  • Nimodipine (Nimotop) is the only drug that has been shown to improve outcome – perhaps cytoprotective?

Cerebral vasospasm

  • Pathophysiology not fully elucidated. Probably multifactorial
  • Blood with its breakdown products is located around the brain where the blood vessels go
  • Provides inflammatory activation, coagulation and endothelial effects
  • Vasoconstriction can be seen as caliber changes in arteries
  • Decreased cerebral perfusion distal to the spasm
  • May be reversible or cause permanent damage with manifest infarction

SAB – Vasospasm – diagnostics

  • Clinical neurological examination is best
  • Symptoms – may fluctuate
  • Increasing headache
  • Incipient Hemiparesis (Positive Grasset)
  • Decreasing level of consciousness
  • Increasing confusion / personality change / aggression
  • Motor anxiety
  • TCD (transcranial Doppler) performed daily to measure flow rates is the only monitoring on anesthetized patient

Transcranial doppler

  • Measures blood flow rate in the blood vessels of the brain
  • At high speeds it may be because the vessel contracts = smaller diameter
  • Values > 2 m/sec may indicate vasospasm
  • Many sources of error and are non-specific
  • Note the effect of increased cardiac output!

In case of suspected vasospasm

  • CT angio – detects caliber changes in the vessels
  • Perfusion CT – can identify if the perfusion is impaired
  • Conventional angiography
  • Angiography of the vessels of the brain, see vasospasm. Simultaneous treatment possible.

Vasospasm at ICU – time to gear up !!

Before vasospasm

  • Nimodipine (Nimotop)
  • Normovolemia
  • No prophylactic fluid beyond the basic need
  • Negative fluid balance to prevent weight gain, as a guideline – 500 ml/day
  • Normonatremia 137-146 mmol/L

Vasospasm

  • Increased nimodipine dose
  • Normovolemia
  • Induced hypertension, SBP> 140 mmHg
  • Monitoring of global hemodynamics with fill targets and cardiac index in the upper reference range
  • If necessary, fluids; Ringer’s – lactate and albumin may be used
  • Avoid vasopressors
  • Avoid hyponatremia
  • Avoid continued edema development = high ELWI
  • Rarely treat high blood pressure

Proposed procedure for targeted circulation optimization in cerebral vasospasm

Systemic complications – SAB is not just a disease of the brain…

Increased sympathetic activity

  • Cardiac stress with risk of heart failure
  • Acute lung injury
  • Pulmonary edema

Systemic inflammatory response syndrome (SIRS) with elevated levels of inflammatory cytokines in the blood

  • Fever
  • Tachypnea – increased respiratory rate
  • Tachycardia
  • Leukocytosis

Circulation and respiration

  • About 15% develop heart failure
  • Stress cardiomyopathy / Takotsubo cardiomyopathy
  • Occurs due to catecholamine supplementation during bleeding
  • More common in women (about 85%)
  • High troponin or NT-proBNP levels
  • ECG changes
  • Low blood pressure/a lot of norepinephrine
  • SAH can also provide so-called neurogenic pulmonary edema (5-10%)

Disorders in the fluid and electrolyte balance

  • Keep track of fluid balance and weight development
  • Normovolemia is the goal
  • Avoid excessive fluid supply!
  • Avoid weight gain in the first 24 hours (means fluid balance target: – 500 ml/d)
  • Give crystalloids in combination with colloids (albumin)
  • Many sodium disorders have an iatrogenic element but SIADH, CSWS, DI and other endocrine disorders occur
  • Diagnose, investigate and analyze first – treat later!

Examples of fluid balance and sodium disorders

SIADH

  • Hyponatremia
  • Fluid retention
  • Weight gain or no weight loss

Diabetes insipidus

  • Hypernatremia
  • Fluid loss

CSWS (Cerebral salt wasting syndrome)

  • Hyponatremia
  • Dehydration
  • Reduced weight

Iatrogenic fluid imbalance

  • Hyponatremia
  • Hypotonic solutions/water intake
  • Patients who are past their risk of spasm must be allowed to return to the fluid balance if he/she has an excess of fluid – which is usually seen as no weight loss during the care period.
  • Common ways to calculate fluid balance are very blunt!
  • +/- 0 in Fluid Balance (FB) means that over time the patient collects fluid

General intensive care principles

  • As little sedation as possible to enable accurate neurological evaluation
  • Supported ventilation – no hyperventilation here!
  • Thrombosis prophylaxis, including mechanical bone pumps
  • Ulcer prophylaxis
  • Antibiotics for the indication and treatment of fever> 38 degrees
  • Mobilization after strength after secured aneurysm
  • Bed position on vasospasm

Different phases during the Neuro-ICU period

  • Acute phase before the aneurysm is secured
    • Bleeding is the biggest threat > peace and quiet! Tranexamic acid!
    • Cardiorespiratory failure may be pronounced
  • Spasm phase on day 3-14
    • Focus on preventing and early treatment of possibly emerging vasospasm. Nimodipine!
    • Hydrocephalus development
    • Problems secondary to ICU care; infections
  • Recovery
    • Settlement of possible V-drain if possible
    • Recovery of normal fluid balance
    • Mobilization and oral nutrition and Nimodipine tablets

Outcome for patients with SAB

  • About 10% of patients die before they go to hospital.
  • Mortality 20-25%
  • 15% have severe neurological loss
  • 55% become independent
  • Cognitive dysfunction is common as well as persistent mental fatigue even in those with good outcomes.

The scientific support behind SAH care (AHA guidelines 2012)

To prevent rebleeding

  • Check blood pressure for high with short-acting drugs (IB)
  • Lower blood pressure SBP < 160 mmHg
  • Give Tranexamic acid (Cyclocapron) within 72 hours

To prevent DCI (Delayed cerebral ischemia)

  • Normovolemia (IB)
  • Prophylactic hypervolemia should be avoided
  • Nimodipine (IA)
  • Following TCD is reasonable
  • Treat fever

For those with DCI symptoms

  • Induce hypertension in those who do not have it (IB)
  • Treat anemia about risk of ischemia, Hb limit?
  • Perform perfusion CT
  • Cerebral intraarterial vasodilation if not reversible with hypertension

Other complications

  • Avoid hypotonic solutions and vasopressors
  • Correct hyponatremia
  • Monitor volume status and global hemodynamics in selected patients
  • Normotherm
  • Glucose control
  • Identify and treat HIT and DVT (IB)

Neurointensive care for traumatic brain injury (TBI)

By Helena Hergés Odenstedt, Chief Physician, in Anesthesia & Intensive Care.

Sahlgrenska University Hospital, Gothenburg, Sweden.

Updated 2020-12-28


What sequelae a patient gets after a traumatic brain injury is a consequence of the primary injury at the time of the injury and the secondary injury mechanisms that develop during the first hours and days after the primary injury. The main goal of neurointensive care is to limit the secondary damage.

Traumatic Brain Injury (TBI)

  • Incidence: 200-450/100,000 inhabitants and year (Swedish data)
  • Traffic accidents dominate
  • 75% men
  • About 50% are over 50 years old
  • TBI is the most common cause of death for people < 40 years

If the patient before hospital has a systolic blood pressure < 90 mmHg and oxygen saturation below 90%, it results in a worse outcome.

Types of injuries – primary brain injury

  • Epidural hematoma
  • Subdural hematoma
  • Brain contusions
  • DAI damage

The emergency care is controlled by

  • Degree of consciousness
  • Neurological status
  • Radiological image
  • Other injuries
  • Clinical course
  • ABCDE applies !!

Prevent secondary brain damage

  • Lower ICP by counteracting edema development
  • Reduce stress response/sympathetic activity
  • Reduce the need for oxygen through reduced metabolism
  • Guarantee adequate oxygen delivery to the brain
  • Adequate O2 supply to the brain
  • Hb ≥ ~ 12 g/dL
  • pO2 ≥ 12 kPa
  • Controlled ventilation
  • pCO2 4.5 – 5 kPa, UK, “optimal” PEEP

You can intervene and control

  • The O2 need
  • Reduce metabolism through sedation and temperature control
  • Reduce the development of cerebral edema
  • Attenuate sympathetic activity by; β-blockade, α-blockade (metoprolol, clonidine)
  • Optimize electrolyte and fluid balance
  • Normalize blood pressure (age dependent)

Prevent secondary complications due to intensive care from:

  • Ventilator treatment; VILI, VAP, trackeostomy
  • Immobilization; Venous thromboembolism
  • Infections; catheter-related infections, VAP
  • Toxic effects of drugs; Propofol, Thiopentone (barbiturates)

A closed room can only hold a certain volume

What competes with the space in the skull is…

  • Brain parenchyma
  • CSF
  • Arterial blood
  • Venous blood

Any additional expansiveness

  • Tumor
  • Bleeding

Factors affecting intracranial dynamics

What can we influence/what matters?

Volume regulation of brain tissue

  • The blood-brain barrier
  • Transcapillary hydrostatic pressure
  • Crystalloid osmotic pressure
  • Plasma oncotic pressure
  • Intracellular edema due to eg ischemia

Volume control of CSF

  • Drainage of cerebrospinal fluid

Cerebral blood volume

  • Change of position, head end height
  • Outflow obstruction; head twisting, high intrathoracic pressure > ICP

Cerebral blood flow

  • Autoregulation
  • PCO2
  • Metabolism
  • Sedation
  • Body temperature

Blood-brain barrier 

  • The most important factor in regulating brain volume
  • Normally only permeable to H2O
  • Liquid transport is governed by differences in
    • Hydrostatic pressure
    • Crystalloid and colloidosmotic pressure

Therefore, we correct

  • Hyponatremi
  • Hypoalbuminemi
  • Anemi

Normally, only H2O passes freely between the bloodstream and the interstitial space. The permeability of albumin, NaCl and mannitol is low. Hydrostatic pressure (MAP) pushes water out of the bloodstream. It dilutes the small and large osmotically active substances in the interstitium while concentrating in the bloodstream and the concentration gradient causes water to be drawn back into the bloodstream.

Damaged blood-brain barrier

  • May occur in parts of the brain
  • Permeability increases for small molecules
  • Later also large molecules
  • Then crystalloid and colloidosmotic pressure becomes less important

Autoregulation

Cerebral blood flow is constant above normal blood pressure.

Unless otherwise is stated, the following applies to head-injured patients in intensive care

  • ICP < 20 mm Hg
  • CPP > 60 mm Hg
  • MAP > 70 mm Hg
  • pO2 12-16 kPa
  • Normovolemia with negative fluid balance
  • pCO2 within normal limits
  • Hb > 10 g/dL
  • S-Na within normal limits
  • S-Alb within normal limits
  • B-Glucose 6-10
  • Normotherm
  • Height head end 10-30 degrees – NOTE what will be the perfusion pressure !!

Head Injury Care – Step 1

  • Means that one aims at the basic treatment goals
  • For patient > RLS 3 the airway is secured and the patient is “comfort sedated”
  • ICP monitoring is initiated. Until then, the patient should be evaluated through regular sedation stops and/or CT scans
  • Normal physiological parameters apply here regarding ventilation, circulation, fluid, Hb, electrolytes etc.
  • If you do not have ICP control with Step 1, you proceed to Step 2, but first make the assessment of whether existing hematomas or contusions should/can be evacuated

Head Injury Care – Step 2

  • Sedation is therapeutic (RASS -4) to lower metabolism, reduce stress and thus control ICP
  • Propofol + fentanyl + midazolam
  • V-drains are considered to have the possibility of liquor drainage/liquor draining.
  • Specific stress reduction to counteract sympathetic activation β-blockade and α-agonist (clonidine)
  • Osmotic therapy
  • Hypertonic Sodium Chloride
  • Electrolytes, ventilation and Hb are controlled even more carefully
  • If not ICP control, Step 3 is considered after taking a position on any. evacuation of hematoma / contusions

Head Injury Care – Step 3

  • All steps along the way are exhausted and the patient is pharmacologically, physiologically and surgically optimized
  • Continuous sedation with intravenous barbiturates – “Pento barbiturate coma” which provides metabolically induced vasoconstriction
  • Is associated with a high risk of complications and is not relevant for all patients
  • Requires continuous EEC monitoring
  • Thiopentone is given until ICP control is achieved and not to specific sleep depth, however max burst supression for the shortest possible time
  • Decompressive cranectomy can be used in isolated cases in case of therapy failure, but the value of it is uncertain and up to the responsible neurosurgeon to assess.

Decompressive craniectomy

Prophylactic hypothermia

Normothermia is optimal

  • Fever > 38 degrees should be treated
  • Paracetamol (acetaminophene) can be given
  • Active infection investigation and treatment for indication
  • In a deeply anesthetized patient, active normothermia 36-37 degrees may be considered
  • No steroids are given on this indication!

Hyperosmolar therapy

We use

  • Mannitol 200 – 300 ml is given before surgery
  • Hypertonic saline can be given as a bolus during 20 min
  • 80 mmol Sodium in 250 ml Socium Chloride – give almost 120 mmol Sodium extra

CSF drainage

  • Open ventricular drain with intermittent measurement
  • Closed ventricular drain with intermittent drainage / “drip” when needed
  • Closed ventricular drain

How do we do?

  • The setting of the ventricular drain is prescribed by a neurosurgeon, but changes must always be communicated to the intensive care physician.

Ventilation

  • VKTS (ventilation mode): 6 ml/kg IBW
  • PEEP: 10 cm H2O or as needed
  • PaO2: 12-16 kPa
  • PaCO2: standard ventilation is the basic rule (4.6-6.0 kPa)
  • In ICP problems: PaCO2 in the lower normal range 4.0-4.5-5.0
  • Short-term hyperventilation on the way to surgery to PaCO2 3.5 – not lower

Anesthesia / Sedation / Pain relief

  • Sedation on 3 levels:
    • Comfort sedation: propofol, fentanyl
    • Therapeutic sedation: (propofol,) fentanyl, midazolam
    • Barbiturate based sedation: (propofol), fentanyl, midazolam, thiopentone

Steroids

  • Not recommended for traumatic brain injury

Nutrition

  • Use a nutrition calculator and adjust the nutrition level as needed and the sedation depth; 15-20-25 kcal/kg
  • Uses Glucose 5% only for a maximum of 7 days
  • Enteral nutrition as far as possible

Infection prophylaxis

  • Trackeostomy when ICP has stabilized for those patients where we suspect long-term ventilator need or slow neurological recovery

Thrombosis prophylaxis

  • Dalteparine (LMWH) 2500 E x 1 sc for almost everyone
  • Supportive socks
  • Mechanical leg pumps

Epilepsy prophylaxis

  • We do not give any antiepileptic drugs prophylactically
  • On suspicion of EP, Bensodazepines are given
  • In case of repeated seizures, do EEG and insert levetiracetam (Keppra)

ICP monitoring

  • ICP monitoring is initiated for patients who are at RLS ≥ 4 and still anesthetized

CPP monitoring

  • When ICP monitoring is available, CPP is calculated as MAP ICP

Advanced cerebral monitoring

  • Jugular bulb monitoring – not used routinely
  • Jugular venous saturation below 50% should be avoided

Recommended blood pressure limits

  • MAP> 70 mm Hg
  • Alternatively the MAP required for CPP > 60 mm Hg
  • Before ICP measurement, it is reasonable to keep MAP > 80 mmHg

ICP limits

  • ICP target < 20 mm Hg
  • If ICP exceeds 22 mm Hg, active treatment is recommended
  • CPP target > 60 mm Hg

Sodium and fluid balance disorders in brain damage

Sodium and fluid balance disorders in brain damage

 SodiumFluid balanceWeightSerum osmolarityOsmolarity in urineTreatment measure
Salt wasting syndromeNegativeNegativeFludrocortisone acetate 0.1 mg x 2
SIADHPositivePositiveFluid restriction
Furosemide
Diabetes insipidusNegativeNegativePossibly Desmopressin
Hypotonic fluid
"Iatrogenic fluid imbalance"PositivePositiveNote water intake,
Possibly NaCl tablets 2 x 3