Posted by Fredrik Bergman, Senior Physician in Anesthesia & Intensive Care. Sahlgrenska University Hospital.
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)
- 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
- 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.
- 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
- 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
- Food poisoning (Bacillus Cereus et al)
- Liver disease – Sepsis, tropical diseases, etc.
- Miliar TBC
- Wilson’s disease (Copper storage in the liver)
- 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
- 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)
- Non-Hodgkin’s lymphoma
- Hodgkin’s disease
- Malignant melanoma
- Malignant histiocytosis
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
|Encephalopathy||No Encephalopathy||Grade 1-2||Grade 3-4|
|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 points||7-9 points||10-15 points|
|Category:||Child Class A||Child Class B||Child Class C|
|Five year survival:||80 percent||50 percent||35 percent|
|Life Expectancy:||15-20 years||Indication for transplant evaluation||1-3 years|
|Abdominal surgery peri-operative mortality:||10 percent||30 percent||82 percent|
- 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.
- 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
- 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)
- 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
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
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:
- 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.
- 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.
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.
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
|Grade||Clinical Features||Neurological Signs||GCS|
|0/subclinical||Normal||Only seen on neuro psychometric testing||15|
|1||Trivial lack of awareness, shortened attention span||Tremor, apraxia, incoordination||15|
|2||Lethargy, disorientation, Personality change||Asterixis, ataxia, dysarthria||11-14|
|3||Confusion, somnolence, Semi-stupor, responsive to stimuli, fits of rage||Asterixis, ataxia||8-10|
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).
- If the arterial ammonium ion is more than 150 micromol/l for more than 24 hours.
- In case of pronounced hyponatraemia (less than 130 mmol/l)
- Abnormal pupil reflexes or precense of seizures
- Encephalopathy 3-4 or when the patient is placed in the respirator.
- Three out of four SIRS criteria
- 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
- Keep high serum tonicity (S-Sodium 145-155 mmol/L)
- Early CRRT with high flows (CVVH setting). Follow ammonium ion.
- Elevate head end to 30 degrees.
- Normoventilation with adequate oxygenation (PO2 > 12 kPa).
- Β-glucose 6-8 mmol/l
- Normal temperature
- 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
- Increase sedation: induces hypometabolic vasoconstriction in the brain
- 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).
- 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.
- Induce mild hypothermia: (may, however, have other negative consequences eg poorer coagulation, etc.)
- Hyperventilation to gain some time.
- NSAIDs (indomethacin 0.5 mg/kg iv) may be considered in manifest intracranial hypertension with documented cerebral hyperemia.
- Barbiturates are not recommended for ALF with high ICP but may be tested for therapy-resistant intracranial hypertension.
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.
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:
- Keep MAP> 65 mmHg
- Give volume such as Albumin in the first place, crystalloids in the other hand, avoid starch solutions.
- If vasopressors are needed for adequate MAP, norepinephrine is the first choice.
- Terlipressin can be added as needed.
- Expand hemodynamic monitoring when needed (PICCO, Swan-Ganz, etc.).
- In therapy-resistant hypotension, hydrocortisone may be tested.
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:
- Keep MAP > 70 mmHg (slightly higher than the above recommendation).
- Try to avoid positive fluid balance.
- Measure abdominal pressure
- 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).
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.
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.
- Acute Liver Failure Lancet 2010;376:190-201. W Bernal, G Auzinger, Julia Wendon.
- Acute Liver Failure NEJM 369;26 NEJM.ORG December 26, 2013 W Bernal, J Wendon.
- Critical Care in Acute Liver Failure (Roger Williams and Julia Wendon) 2013. Future Medicine. ISBN: 978-1-78084-257-8
- Acute hepatic failure (PACT 2012) Chris Willars and Julia Wendon.
Posted by Ann-Charlotte Loswick, Senior Physician in Anesthesia & Intensive Care. Sahlgrenska University Hospital.
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||
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
- Levemir has a duration of about 15-20 hours.
- Lantus and Abasalgar have a duration of about 20-28 hours.
- 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
2. Tablet Controlled Diabetes
Diabetes mellitus - Tablet Controlled Diabetes
3. Insulin Treated Diabetes
Diabetes Mellitus - Insulin Treated Diabetes
4. Patients with an insulin pump. Typ 1 Diabetes. Fast acting Insulin.
Diabetes Mellitus - Patients with Insulin Pump
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.
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.
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)
The most important treatment is fluid, insulin and adequate potassium supply.
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.
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.
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 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!
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
- 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.
- Chua et al. J Crit Care. 2012;27:138-45
- Mahler et al. Am J Emerg Med. 2011;29:670-4
- Van Zyl et al. QJM. 2012;105:337-43
- Ma et al, Pediatr Crit Care Med. 2014 Oct;15(8)
- Tasker et al, Pediatr Diabetes. 2014 Jun;15(4):261-70.
- Glaser et al, Journ Pediatr. 2004 Aug;145(2):164-71
- Kitabchi et al. Diabetes Care. 2009;32:1335-43.
- Adrogué HJ et al, J Am Soc Nephrol 2004; 15:1667
- Glaser et. al. N Engl J Med 2001 Jan 25;344
- Glaser et. al. N Engl J Med 2001 Jan 25;344
- Viallon et al. Crit Care Med. 1999;27:2690-3
- Glaser et. al. N Engl J Med 2001 Jan 25;34
Posted by Hanna Drougge, Specialist Physician in Anesthesia & Intensive Care, Sahlgrenska University Hospital.
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.
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.
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.
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.
- Chantzichristos et al., Health Care Program for Hyponatraemia, 2012.
- Spasovski et al. Clinical Practice Guideline on Diagnosis and Treatment of Hyponatremia. Eur J Endocrinol. 2014 Feb 25; 170 (3): G1-47
- Verbalis et al., Diagnosis, Evaluation, and Treatment of Hyponatremia: Expert panel recommendations. Am Journal of Med 126: S5-S42
Posted by Kai Knudsen, Senior Physician in Anesthesia & Intensive Care, Sahlgrenska University Hospital.
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.
Posted by Kai Knudsen, Senior Physician in Anesthesia & Intensive Care, Sahlgrenska University Hospital.
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 loss||Non-Renal Causes|
|With Hypertension||With normal blood pressure|
|Cushing syndrom||Renal tubular acidosis||Alkalosis||Intestinal losses|
|Congenital adrenal hyperplasia||Fanconi syndrome||Leucemia||Diarrhéa|
|Primary hyperaldosteronism||Bartter's syndrom||Familiar hypokalemic periodic paralysis||Laxatives|
|Increased amount of renin||Diabetic keto acidosis||Sweating||Enema|
|Renovascular disease||Antibiotics||Anorexia nervosa|
|Urinary K > 20 mmol /L||Urinary 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.
Posted by Gunilla Islander, Senior Physician in Anesthesia & Intensive Care, Skåne University Hospital, Lund.
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
- Potent Inhalation Anesthetics
- Isoflurane (Forene®)
- Sevoflurane (Sevorane®)
- Desfluran (Suprane®)
- Older Inhalation Anesthetic Substances (Halothane®, Enfluran®, Ether, etc.)
- 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
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
- 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
- Difficulty tachycardia
- Arythmia (eg ectopic ventricular stroke, VES in bigemini)
- Instant blood pressure
- 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
- Too light anesthesia
- 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 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
- 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.
- 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.
- 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
- Blood sugar
- Liver Status
- 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.
- 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.
- 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.
- 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.
- Glahn KP et al. Recognizing and managing a malignant hyperthermia crisis: guidelines from the European Malignant Hyperthermia Group. Br J Anaesth. 2010 Oct; 105 (4): 417-20.
- Rosenberg H, et al. Malignant hyperthermia: a review. Orphanet J Rare Dis. 2015; 10: ’93.
- Hopkins PM, et al. European Malignant Hyperthermia Group guidelines for the investigation of malignant hyperthermia susceptibility. Br J Anaesth.2015 Oct; 115 (4): 531-9.
- 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
Figure 1. Investigation and treatment of acute massive pulmonary embolism.
Posted by Katalin Kiss, Senior Physician in Anesthesia & Intensive Care, Sahlgrenska University Hospital.
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.
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.
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) potential||Mineral Corticoid Potential||Biological Half-time (hours)|
|Hydrocortisone||20||1||2||8 - 12|
|Prednisolone||5||4||1||18 - 36|
|Methylprednisolone||4||5||0||18 - 36|
|Betapred||0.75||30||0||36 - 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.
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
Posted by Kai Knudsen, Senior Physician in Anesthesia & Intensive Care, Sahlgrenska University Hospital.
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.
- 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 action||Adjust the drop rate||New sample checked|
|> 200 sec||>160 sec||Check the infusion mixture. Take a new test APTT sample, turn off the drop for 1 hour (not the first APTT after drip start)||Reduce at 9 ml/h||New test after 4 hours|
|181-200 sec||141-160 sec||Reduce at 9 ml/h||New test after 6 hours|
|141-180 sec||111-140 sec||Reduce at 6 ml/h||New test after 6 hours|
|121-140 sec||81-110 sec||Reduce at 3 ml/h||New test after 6 hours|
|60-120 sec||50-80 sec||Unchanged infusion rate||If the first value after drip start, take a new test after 6 hours, or after 12 hours.|
|50-59 sec||40-49 sec||Increase at 2 drops/min (= 6 ml/h)||New test after 6 hours|
|< 50 sec||< 40 sec||Give 2500 E of Heparin i.v. and||Increase infusion rate at 9 ml/h||New test after 6 hours|
Anticoagulation. Deep vein thrombosis (DVT), pulmonary embolism. Intravasal coagulation, peritendinitis crepitans. Extracorporeal circulation associated with cardiovascular surgery and hemodialysis.
Haemorrhage, thrombocytopenia, transient liver effect.
5000 IU/ml, 25,000 IU/ml.
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.