JUGULAR VENOUS BULB SATURATION 203 Formulas ) \216 \216 \227( \227 \216 \216 = \227 \200\223 SaO SjO 2 CM RO CBF 1.34 Hb 2 2 \200 where CMRO2 = cerebral metabolism of oxygen CBF = cerebral blood \202 ow SjO2 = ju gular bulb oxygen saturation SaO2(%) = arterial oxygen saturation \216\233 \216\234 \216\235 \216\236 \216\237 \216 \210\222 SaO SjO 2 jjO2 S = 2 Cerebral oxygen extraction ratio Cerebral perfusion pressure = systemic BP \200\223 intracranial pressure See also: Intracranial pressure monitoring, p200; Other neurological monitoring, p206; Intr acranial hemorrhage, p448; Subarachnoid hemorrhage, p450; Raised intracranial pressure, p45 4; Head injury (1), p586. 204 CHAPTER 10 Neurological monitoring EEG/CFM monitoring EEG monitoring The EEG re \202 ects changes in cortical electrical func tion. This, in turn, is dependent on cerebral perfusion and oxygenation. EEG monitoring can be useful to assess epileptiform activity as well as cerebral well-being in patients who a re sedated and paralyzed. The conventional EEG can be used intermittently, but data reducti on and artifact suppression are necessary to allow successful use of EEG recordings in the ICU. Bispectral index (BIS) monitor BIS is a statistical index derived from the EEG and expresse d as a score between 0 \200\223100. Scores below 50 have been reliably associated with anae s- thesia-induced unconsciousness. Assessment in the critically ill patient may be complica ted by various confounding factors such as septic encepha- lopathy, head trauma, and hypope rfusion. A low score is related to deep or excessive sedation, and may allow dose reduction (or cessation) of sedative agents, especially in paralyzed patients. Cerebral function monitor (CFM) The CFM is a single channel, \201 ltered trace from two r ecording electrodes placed over the parietal regions of the scalp. A third electrode may be used in the midline to help with interference detection. The parietal recording electrodes are usually placed close to watershed areas of the brain in order to allow maximum sensiti vity for ischaemia detection. Voltage is displayed against time on a chart running at 6 \200\22330cm/h. 50 25 Cerebral ischaemia Complete loss of cerebral activity V 10 5 0 time Fig. 10.1a Typical CFM recording in cerebral ischaemia. Use of CFM The CFM may detect cerebral ischaemia; burst suppression (periods of increasingl y prolonged electrical silence) provides an early warning (see \201 gure 10.1a). 50 Sedative 25 V 10 5 0 time Sedation produces a fall in baseline to <5 V, equivalent to burst suppression. This is equ ivalent to maximum reduc- tion in cerebral VO2 and no further bene \201 t would be gained from additional sedation (see \201 gure 10.1b). Seizure activity 50 25 V 10 5 Seizure activity may be detected in patients despite apparently adequate clinical control o r where muscle relax- ants have been used (see \201 gure 10.1c). 0 time Fig. 10.1b-c Typical CFM record- ings in sedation (b) or during seizure activity (c). EEG/CFM MONITORING 205 50 Smooth fluctuation (sleep changes, cerebral responses \200\223Good prognosis 25 V 10 5 0 time 50 25 V 10 5 Abrupt changes in baseline \200\223Brainstem dysfunction 0 time 50 25 V 10 5 Monotonous \200\223Poor prognosis 0 time 50 25 V 10 5 Downward sawtooth \200\223Poor prognosis 0 time 50 25 V 10 5 Upward sawtooth \200\223Poor prognosis 0 time 50 Flat \200\223Poor prognosis (if not due to sedation or hypothermia) 25 V 10 5 0 time Fig. 10.2 Typical CFM patterns. See also: Sedatives and tranquilisers, p308; Coma, p438; Generalized seizures, p444; Head i njury (1), p586; Head injury (2), p588; Hypothermia, p606; Brain stem death, p652. 206 CHAPTER 10 Neurological monitoring Other neurological monitoring Cerebral blood \202 ow (CBF) CBF can be measured by radiois otope techniques utilizing tracers such as xenon-133 given intravenously or by inhalation. This remains a research tool in view of the radioactivity exposure and the usual need to mo ve the patient to a gamma-camera. However, portable monitors are now available. Middle cerebral artery (MCA) blood \202 ow can be determined non- invasively by transcran ial Doppler ultrasonography. The pulsatility index (PI) relates to cerebrovascular resistan ce, with a rise in PI indicating a rise in resistance and cerebral vasospasm. Vasospasm can also be diagnosed when the MCA blood \202 ow velocity exceeds 120cm/s and s evere vasospasm when velocities >200cm/s. Low values of common carotid end-diastolic blood \202 ow and velocity have been shown to be highly discriminating predictors of brain deat h. Impaired reactivity of CBF to changes in PCO2 (in normals 3 \200\2235% per mmHg PCO2 cha nge) is another marker of poor outcome. Near-infrared spectroscopy (NIRS) \200 Near-infrared (700 \200\2231000nm) light propagated across the head is absorbed by hemoglob in (oxy- and deoxy-), myoglobin, and oxidized cytochrome aa3 (the terminal part of the resp iratory chain involved in oxidative phosphorylation). The sum of (oxy- + deoxy-) hemoglobin is considered an index of cerebral blood volume (CBV) change, and the difference as an ind ex of change in hemoglobin saturation assuming no variation occurs in CBV. CBV and \202 o w can be quanti \201 ed by changing the FIO2 and measuring the response. Cerebral blood \202 ow is measured by a modi \201 cation of the Fick principle. Oxyhaemoglobin is the int ravascular non-diffusible tracer, its accumulation being proportional to the arterial in \202 ow of tracer. Good correlations have been found with the xenon-133 technique. Cytochro me aa3 cannot be quanti \201 ed by NIRS, but its redox status may be followed to provide s ome indication of mitochondrial function. Movement artifact must be avoided and some device s require shielding from ambient lighting. Lactate The brain normally utilizes lactate as a fuel. However, in states of severely impai red cerebral perfusion, the brain may become a net lactate producer with the venous lactate rising above the arterial value. A lactate oxygen index can be derived by dividing the ven o-arterial lactate difference by the arterio-jugular venous oxygen difference. Values >0.08 are consistently seen with cerebral ischaemia. Cerebral microdialysis Microdialysis catheters may be placed in the brain during surgery to assess brain metabolism. Extracellular \202 uid chemicals diffuse into the catheter and are sampled for bedside analysis of, e.g. glucose, lactate, and pyruvate. An elevated extra cellular \202 uid lactate:pyruvate ratio is a sensitive marker of ischemia following acut e brain injury. The technique can monitor tissue at risk of ischaemia, e.g. due to vasospas m, or to determine the safe lower limit of cerebral perfusion pressure. OTHER NEUROLOGICAL MONITORING 207 See also: Tissue perfusion monitoring, p194; Lactate, p236. This page intentionally left blank 209 Chapter 11 Laboratory monitoring Urea and creatinine 210 Electrolytes (Na+, K+, Cl \200\223, HCO3 Calcium, magnesium, and ph osphate 214 Cardiac function tests 216 Liver function tests 218 Full blood count 220 Coagul ation monitoring 222 Bacteriology 224 Virology, serology, and assays 226 Toxicology 228 \200\223) 212 210 CHAPTER 11 Laboratory monitoring Urea and creatinine Measured in blood, urine and, occasionally, in other \202 uids such a s abdom- inal drain \202 uid (e.g. ureteric disruption, \201 stulae). Urea A product of the urea cycle resulting from ammonia breakdown, it depends upon adequate liver function for synthesis and adequate renal function for excretion. Low levels are see n in cirrhosis and high levels in renal failure. Uraemia is a clinical syndrome, including lethargy, drowsiness, confu- sion, pruritus, and pericarditis resulting from high plasma levels of urea (or, more correctly, nitrogenous was te products \200\224azotaemia). The ratio of urine:plasma urea may help to distinguish oliguria of renal or pre-renal origi ns. Higher ratios (>10:1) occur in pre-renal conditions e.g. hypovolaemia, while low levels (<4:1) occur with direct renal causes. 24h measurement of urinary urea (or nitrogen) excretion has been pre- viously used as a gui de to nutritional protein replacement, but is currently not considered a useful routine too l. Creatinine A product of creatine breakdown, it is predominantly derived from skeletal muscl e and is also renally excreted. Low levels are found with malnutrition and high levels with muscle breakdown (rhabdomyolysis) and impaired excretion (renal failure). In the latter ca se, a creatinine value >120 mol/L suggests a creatinine clearance <25mL/min. The usual ratio for plasma urea (mmol/L) to creatinine ( mol/L) is approximately 1:10. A m uch lower ratio in a critically ill patient is suggestive of rhabdomyolysis whereas higher ratios are seen in cirrhosis, malnutrition, hypovolaemia, and hepatic failure. The ratio of urine:plasma creatinine may help distinguish between olig- uria of renal or pr e-renal origins. Higher ratios (>40) are seen in pre-renal conditions and low levels (<20) with direct renal causes. Creatinine clearance Creatinine clearance is a measure of glomerular \201 ltration. Once \201 ltered, only small amounts of creatinine are re-absorbed. U \227 V \227 1000 P \227 T U is urine creatinine (mmol/L) V is urine volume (mL) P is p lasma creatinine ( mol/L) T is time of urine collection (min) Creatinine clearance = \200 where UREA AND CREATININE 211 Normal plasma ranges Urea Creatinine Creatinine clearance male Creatinine clearance female 2.5 \200\2236.5mmol/L 70 \200\223120 mol/L (depends on lean body mass) 85 \200\223125mL/mi n 75 \200\223115mL/min See also: Oliguria, p398; Acute renal failure \200\224diagnosis, p400. 212 CHAPTER 11 Laboratory monitoring Electrolytes (Na+, K+, Cl \200\223, HCO3 \200\223) Measured accurately by direct-reading, ion-speci \201 c electrodes from plasma or urine, t hough they are sensitive to interference by excess liquid heparin. Sodium, potassium Plasma levels may be elevated, but poorly re \202 ect intracellular (app roxi- mately 3 \200\2235mmol/L for Na+, 140 \200\223150mmol/L for K+) or total body levels. Plasma potassium levels are affected by plasma H+ levels; a metabolic acidosis reduces uri nary potassium excretion while an alkalosis will increase excretion. Older measuring devices such as \202 ame photometry or indirect-reading, ion-speci \201 c electrodes gave spuriously low plasma Na+ levels with concur- rent hyperproteinaemia or h ypertriglyceridaemia. Urinary excretion depends on intake, total body balance, acid-base balance, hormones (inclu ding antidiuretic hormone, aldosterone, cortico- steroids, atrial natriuretic peptide), dru gs (particularly diuretics, non-steroidal anti-in \202 ammatories, and ACE inhibitors), an d renal function. In oliguria, a urinary Na+ level <10mmol/L suggests a pre-renal cause whereas >20mmol/L is seen with direct renal damage. This does not apply if diuretics have been given previously. Chloride, bicarbonate Bicarbonate levels vary with acid-base balance. In the kidney, Cl \200\223 reabsorption is increased when HCO3 \200\223 reabsorption is decreased, and vise versa. Plasma [Cl \200\223] thus tends to var y inversely with \200\223], keeping the total anion concentration normal. A raised plasma [HCO3 [Cl \200\223] (producing a hyperchloraemic metabolic acidosis) may be seen with admin istration of large volumes of isotonic saline or isotonic, saline-containing colloid soluti ons. Hyperchloraemia is also found with experimental salt water drowning but rarely seen in actual cases. Anion gap The anion gap is the difference between unestimated anions (e.g. phos- phate, ket ones, lactate) and cations. In metabolic acidosis, an increased anion gap occurs with renal failure, ingestion of acid, ketoacidosis, and hyperlactataemia whereas a normal anion gap (usually associated with hyp erchloraemia) is found with decreased acid excretion (e.g. Addison \200\231s disease, renal tubular acidosis) and loss of base (e.g. diarrhea, pancreatic/biliary \201 stula, acetaz olamide, ureterosigmoidostomy). ELECTROLYTES (NA+, K+,CL \200\223, HCO3 \200\223) 213 Normal plasma ranges Sodium Potassium Chloride Bicarbonate 135 \200\223145mmol/L 3.5 \200\2235.3mmol/L 95 \200\223105mmol/L 23 \200\22328mmol/L Anion gap = plasma [Na+] + [K+] \200\223 [HCO3 Normal range 8 \200\22316mmol/L \200\223] \200\223 [Cl \200\223]. See also: Blood gas analysis, p154; Electrolyte management, p482; Hypernatraemia, p484; Hyp onatraemia, p486; Hyperkalaemia, p488; Hypokalaemia, p490; General acid-base principles, p5 00; Metabolic acidosis, p502. 214 CHAPTER 11 Laboratory monitoring Calcium, magnesium, and phosphate Calcium Plasma calcium levels have been traditionally cor rected to plasma albumin levels; this is now considered irrelevant, particularly at the low albumin levels seen in critically ill patients. Measurement of the ionized fraction is now considered more pertinent since it is the ionized fraction that is responsible for the ext racellular actions of calcium, with changes in the ionized fraction being responsible for t he symptomatology. High calcium levels occur with hyperparathyroidism, certain malignancies, and sarcoidosis, while low levels are seen in renal failure, severe pancreatitis, and hypoparathyroidism. Magnesium Plasma levels poorly re \202 ect intracellular or whole body stores, 65% of whic h is in bone and 35% in cells. The ionized fraction is approximately 50% of the total level . High magnesium levels are seen with renal failure and excessive admin- istration; this rare ly requires treatment unless serious cardiac conduction problems or neurological complicati ons (respiratory paralysis, coma) intervene. Low levels occur following severe diarrhea, diuretic therapy, alcohol abuse, and accompany hypocalcaemia. Magnesium is used therapeutically for a number of conditions, including ventricular and sup raventricular arrhythmias, eclampsia, seizures, asthma, and after myocardial infarction. Su pranormal plasma levels of 1.5 \200\2232.0mmol/L are often sought. Magnesium levels tend to follow potassium levels. Hypokalaemia is resistant to treatment unless magnesium is corrected \201 rst. Phosphate High levels are seen with renal failure and in the presence of an ischaemic bowel . Low levels (sometimes <0.1mmol/L) occur with critical illness, chronic alcoholism, and di uretic usage, and may possibly result in muscle weakness, failure to wean, and myocardial d ysfunction. CALCIUM, MAGNESIUM, AND PHOSPHATE 215 Normal plasma ranges Calcium Ionized calcium Magnesium Phosphate 2.2 \200\2232.6mmol/L 1.05 \200\2231.2mmol/L 0.7 \200\2231.0mmol/L 0.7 \200\2231.4mmol/L See also: Hypomagnesaemia, p492; Hypercalcaemia, p494; Hypocalcaemia, p496; Hypophosphataem ia, p498; Pre-eclampsia and eclampsia, p634. 216 CHAPTER 11 Laboratory monitoring Cardiac function tests The diagnosis of myocardial infarction has been rede \201 ned as a typical rise, then fall in troponin, or a more rapid rise and fall in CK \200\223MB, with a t least one of the following: \200 \200 \200 \200 Ischaemic symptoms. Development of pathological Q waves on ECG. ECG ST elevation or depress ion. Coronary intervention. Troponins Troponins are bound to the actin \201 lament within muscles and are involved in excitation-contraction coupling. Both cardiac troponin T and troponin I are coded by speci \201 c genes and are immunologically distinct from those in skeletal muscle. Neither is d etectable in normal healthy individuals, but both are released into the bloodstream from ca rdiomyocytes damaged by necrosis, toxins, and in \202 ammation. They become detectable by 4 \200\2236h after myocardial injury, peak at 14 \200\22318h, and persist for up to 12 days . Current assays are highly speci \201 c as they use recombinant human cardiac tropinin T as a standard. Due to their high sensitivity, plasma levels rise with other cardiac insults, e.g. tachycar dia (SVT/VT), pericarditis, myocarditis, sepsis, heart failure, severe exertion, and pulmon ary embolism. The degree of rise post-MI or during critical illness correlates with a worse outcome. A positive test is when the cardiac troponin T or I exceeds the 99th percentile of values f or a control group on \211 1 occasion during the \201 rst 24h after the index clinical e vent. For cardiac troponin T, this is quoted as 0.05 \200\2230.1ng/mL though many labs now consider values >0.03ng/mL as positive. Values for cardiac troponin I depend on the particu lar assay used (usually >0.5 \200\2231.5ng/mL). The negative predictive value after an acut e MI is probably strongest after 6h. Sensitivity peaks at 12h but at the expense of a lower speci \201 city. With renal dysfunction, higher levels are needed to diagnose myocardial damage due to impaired excretion. Cardiac enzymes Creatine kinase (CK) is detectable in plasma within a few hours of myo- car dial injury. The cardiac-speci \201 c isoform (CK-MB) can be measured if there is concurre nt skeletal muscle injury. CK and aspartate aminotrans- ferase (AST) peak by 24h and fall o ver 2 \200\2233 days whereas the rise and sub- sequent fall in plasma lactate dehydrogenase takes 1 \200\2232 days longer (see \201 gure 11.1). Brain (or B-type) natriuretic peptide (BNP) Cardiomyocytes produce and secrete cardiac natr iuretic peptides. Plasma levels rise in a variety of conditions, but high levels are predom inantly associated with heart failure and increase in relation to severity. A sensi- tivity of 90 \200\223100% is claimed, whereas speci \201 city is approximately 70 \200\22380%. N umerous commercial assays for BNP or proBNP are now available, each with their own diagnost ic range. They are useful as a screening tool for patients presenting with dyspnoea, for pr ognostication, and for titration of therapy. Levels rise in the elderly, in renal failure, and in pulmonary diseases causing right ventricular overload (e.g. pulmonary embolus). CARDIAC FUNCTION TESTS 217 Cardiac troponin after \200\230classic \200\231 AMI 50 r e p p u 20 CK-MB after AMI d e t i 10 Cardiac troponin after \200\230microinfarction \200\231 m e h t i l 5 e c n e r e f e r f o s e p i t l u m Upper reference limit 2 l 1 0 4 Days post-onset of acute myocardial infarction (AMI) 2 6 8 Fig. 11.1 Pattern of troponin and cardiac isoenzyme change after myocardial infarction. Key papers Alpert JS, Thygesen K, Antman E, et al. (2000) Myocardial infarction rede \201 ned \200\224a consensus document of The Joint European Society of Cardiology/American Colle ge of Cardiology com- mittee for the rede \201 nition of myocardial infarction. J Am Coll Cardiol 36: 959 \200\22369. McCullough PA, Nowak RM, McCord J, et al. (2002) B-type natriuretic peptide and clinical ju dgment in emergency diagnosis of heart failure: analysis from Breathing Not Properly (BNP) Multinational Study. Circulation 106: 416 \200\22322. McLean AS, Huang SJ, Salter M. (2008) Bench-to-bedside review: The value of cardiac biomark ers in the intensive care patient. Crit Care 12: 215. See also: Acute coronary syndrome (1), p388; Acute coronary syndrome (2), p390; Heart failu re \200\224 assessment, p392. 218 CHAPTER 11 Laboratory monitoring Liver function tests Hepatic metabolism proceeds via phase I enzymes (oxidation and phos- p horylation), and subsequently, phase II enzymes (glucuronidation, sulpha- tion, acetylation ). Phase I enzyme reactions involve cytochrome P450. Markers of hepatocyte damage \200 Alanine aminotransferase (ALT). \200 Aspartate aminot ransferase (AST). \200 Lactate dehydrogenase (LDH). Patterns and ratios of various enzymes are variable and unreliable diag- nostic indicators. Measurement of ALT alone is usually suf \201 cient. It is more liver-speci \201 c, but l ess sensitive than AST and has a longer half-life. AST is not liver-speci \201 c, but is a sensitive indicator of hepatic damage. The plasma level is proportional to the degree of hepatocellular damage. Low levels occur in extrahepa tic obstruction and inactive cirrhosis. LDH is insensitive and non-speci \201 c. Isoenzymes are needed to distinguish cardiac, erythrocyte, skeletal muscle, and liver injury. Acute phase reactants such as C-reactive protein (CRP) produced by the liver increase durin g critical illness and following hepatocellular injury. Markers of cholestasis \200 \200 \200 Bilirubin. Alkaline phosphatase. Gamma-glutamyltransferase (G-GT). Bilirubin is conjugated with glucuronide by the hepatocytes. The conjugated fraction is wat er-soluble whereas the unconjugated fraction is lipid-soluble. Levels are increased with in tra- and extra-hepatic biliary obstruction (pre- dominantly conjugated), hepatocellular dam age, and haemolysis (usually mixed picture). Jaundice is detected when levels >45 mol/L. Alkaline phosphatase is released from bone, liver, intestine, and placenta. 3 \200\223) and pregnancy, In the absence of bone disease (check Ca2+ and PO4 raised levels usually indicate biliary t ract dysfunction. A raised G-GT is a highly sensitive marker of hepatobiliary disease. Increased synthesis is induced by obstructive cholestasis, alcohol, various drugs and toxins, acute and chronic h epatic in \202 ammation. Markers of reduced synthetic function \200 \200 \200 Albumin. Clotting factors. Cholinesterase. Albumin levels fall during critical illness due to protein catabolism, capil- lary leak, de creased synthesis, dilution with arti \201 cial colloids. Coagulation factors II, VII, IX, and X are liver-synthesized. Over 33% of functional hepatic mass must be lost before any abnormality is seen. Indicators of function \200 Lidocaine metabolites (MegX). Indicators of hepatic blood \202 ow \200 \200 Indocyanine green clearance. Bromosulphthalein clearance. LIVER FUNCTION TESTS 219 Normal plasma ranges Albumin Bilirubin Conjugated bilirubin Alanine aminotransferase Alkali ne phosphatase Aspartate aminotransferase Cholinesterase G-glutamyltransferase Lactate dehy drogenase 35 \200\22353g/L 3 \200\22317 mol/L 0 \200\2236 mol/L 5 \200\22350U/L 100 \200\223280U/L 11 \200\22355U/L 2.3 \200\2239.0kU/L 5 \200\22337U/L 230 \200\223460U/L See also: Jaundice, p428; Acute liver failure, p430; Hepatic encephalopathy, p432; Chronic liver failure, p434; Paracetamol poisoning, p524; HELP syndrome, p636. 220 CHAPTER 11 Laboratory monitoring Full blood count Hemoglobin A raised hemoglobin occurs in polycythaemia (primary and second ary to chronic hypoxaemia) and in haemoconcentration. Anemia may be due to reduced red cell mass (decreased red cell production or survival) or haemodilution. The latter is common in critically ill patients. In severe anemia, there may be a hyperdynamic circulation which, if severe, may decompensate to cardiac failure. In this case, blood transfusion must be per formed with extreme care to avoid \202 uid overload or in association with plasmapheresis . Differential diagnosis of anemia includes: Reduced MCV Raised MCV Iron de \201 ciency (anisocytosis and poikilocytosis) Vitamin B12 or folate de \201 cienc y Alcohol excess or liver disease Hypothyroidism Anemia of chronic disease Bone marrow fail ure (e.g. acute folate de \201 ciency) Hypothyroidism Haemolysis (increased reticulocytes and bilirubin) Normal MCV White blood cells A raised white cell count is extremely common in critical illness. Causes of changes in the differential count include: Neutrophilia Bacterial infection Trauma, surgery and burns Hemorrhage In \202 ammation Cor ticosteroid therapy Leukemia Neutropaenia Viral infections Tuberculosis Sulphonamide treatm ent Severe sepsis Hypersplenism Bone marrow failure Lymphocytosis Brucellosis Typhoid Myasthenia gravis Hyperthyroidism Leukemia Eosinophilia Asthma Allergic conditions Parasitaemia Lymphopaenia Corticosteroid therapy SLE Legionnaire \200\231s disease AIDS Platelets Correct interpretation of platelet counts requires venous (not capil- lary) blood . Arterial blood from an indwelling cannula is not ideal. Thrombocytopaenia is due to decre ased platelet production (bone marrow failure, vitamin B12, or folate de \201 ciency), dec reased platelet sur- vival (ITP, TTP, infection, hypersplenism, heparin therapy), increased platelet consumption (hemorrhage, DIC), or in vivo aggregation giving an apparent thromboc ytopaenia; this should be checked on a blood \201 lm. Spontaneous bleeding is associated with platelet counts <10x109/L and platelet cover is required for procedures or traumatic b leeds at counts <50x109/L. FULL BLOOD COUNT 221 Normal ranges Hemoglobin MCV White cell count Neutrophils Lymphocytes Eosinophils Basophils Monocytes Platelets 13 \200\22317g/dL (men), 12 \200\22316g/dL (women) 76 \200\22396fL 4 \200\22311x109/L 2 \200\2237.5x109/L 1.3 \200\2233.5x109/L 0.04 \200\2230.44x109/L 0 \200\2230.1x109/L 0.2 \200\2230.8x109/L 150 \200\223400x109/L See also: Anemia, p472; Sickle cell disease, p474; Haemolysis, p476; Platelet disorders, p4 78. 222 CHAPTER 11 Laboratory monitoring Coagulation monitoring Basic coagulation screen The basic screen consists of a platelet cou nt, prothrombin time, acti- vated partial thromboplastin time, and thrombin time. Close att ention to blood sampling technique is very important for correct interpretation of coagulat ion tests. Drawing blood from indwelling catheters should ideally be avoided since samples may be diluted or contaminated with heparin. The correct volume of blood must be placed in the sample tube to avoid dilution errors. Laboratory coagulation tests are usually performe d on citrated plasma samples taken into glass tubes. Speci \201 c coagulation tests Activated clotting time (ACT) Sample tube contains celite w hich activates the contact system; thus, the ACT predominantly tests the intrinsic pathway. The ACT is prolonged by heparin therapy, thrombocytopaenia, hypothermia, haemodilution, \201 brinolysis, and high-dose aprotinin. Normal is 100 \200\223140s. Thrombin time (TT) Sample tube contains lyophilised thrombin and calcium. Thrombin bypasses the intrinsic and extrinsic pathways such that the coagulation time tests the common pathw ay with conversion of \201 brinogen to \201 brin. The TT is prolonged by \201 brinoge n depletion, e.g. \201 brinolysis or thrombol- ysis and heparin via antithrombin III-depe ndent interaction with thrombin. A high-dose TT is more sensitive to heparin anticoagulatio n than \201 brinogen levels. Normal is 12 \200\22316s. Prothrombin time (PT) Sample tube contains tissue factor and calcium. Tissue factor activat es the extrinsic pathway. The PT is prolonged with coumarin anticoagulants, liver disease, and vitamin K de \201 ciency. Normal is 12 \200\22316s. The international normalized ratio (INR) relates PT to control and is normally 1. Activated partial thromboplastin time (APTT) Sample tube contains kaolin and cephalin as a platelet substitute to acti- vate the intrinsic pathway. The APTT is prolonged by heparin t herapy, DIC, severe \201 brinolysis, von Willebrand factor, factor VIII, factor XI, or fa ctor XIII de \201 ciencies. Normal is 30 \200\22340s. D-dimers and \201 brin degradation products (FDPs) Fibrin fragments are released by plasm in lysis. FDPs can be assayed by an immunological method; they are often measured in the cr itically ill to con \201 rm disseminated intravascular coagulation. A level of 20 \200\223 40mcg/mL is common post-operatively, in sepsis, trauma, renal failure, pulmonary embolus, a nd DVT. Raised levels do not distinguish \201 brinogenolysis and \201 brinolysis. Assay of the D-dimer fragment is more speci \201 c for \201 brinolysis, e.g. in DIC, since it is only released after \201 brin is formed. Coagulation factor assays Assays are available for all coagulation factors and may be used for diag- nosis of speci \201 c defects. As heparins inhibit factor Xa activity, the facto r Xa assay is the most speci \201 c method of controlling low molecular weight heparin the rapy. COAGULATION MONITORING 223 Initiation FX FVa FVIII FVIIa FIIa FII FVIIa FXa FVa FVIIIa TF TF Activated phospholipid membrane Amplification/thrombin (FIIa) formation FX FII FIIa FVIIa FIX FXa FVa FVIIIa FIXa TF Activated phospholipid membrane Clot formation platelets FIIa fibrinogen fibrin FIIIa FIII activated platelets cross-linked fibrin fibrin + platelet clot TF: tissue factor Fig. 11.2 The coagulation cascade. The traditional coagulation cascade consisting of extrinsic, intrinsic, and common pathways is now considered outmoded, inconsistent with clinical observations, and inadequate to exp lain the pathways leading to haemos- tasis in vivo. This schema has been replaced recently by a cell-based model with the major initiating haemostasis event in vivo being the action of factor VIIa and tissue factor at the site of injury. See also: Intra-aortic balloon counterpulsation, p102; Haemo(dia) \201 ltration (1), p108; Haemo(dia) \201 ltration (2), p110; Plasma exchange, p114; Anticoagulants, p318; Thrombol ytics, p320; Coagulants and anti \201 brinolytics, p322; Pulmonary embolus, p376; Acute li ver failure, p430; Bleeding disorders, p468; Clotting disorders, p470. 224 CHAPTER 11 Laboratory monitoring Bacteriology Microbiology samples should, if possible, be taken prior to commencement of an timicrobial therapy. In severe infections, broad-spectrum antimicrobials should be started without awaiting results. Sampling sites include those suspected clini- cally of harboring infection or, if a speci \201 c site cannot be identi \201 ed clinically, blood, urine, a nd sputum samples. In severe infection, indwelling intravascular catheters should be replac ed and the tips sent for culture. Samples should be sent to the laboratory promptly for ear ly incubation and to prevent potentially misleading growth. Swabs must be sent in appropria te transportation media. Blood cultures In order to avoid skin contamination, the skin should be cleaned with alcoho l/chlorhexidine and allowed to dry thoroughly before venepuncture. A 10 \200\22320mL blood sample is withdrawn and divided into anaerobic and aerobic culture bottles. If catheter-rel ated sepsis is suspected, a catheter sample may be taken. Clearly label all samples. Cultur e bottles are incu- bated and examined frequently for bacterial growth. Positive cultures m ust be interpreted in light of the clinical picture; an early, pure, heavy growth from mult iple bottles is probably signi \201 cant. Cultures from the critically ill may grow later or not at all due to antibiotic therapy. Any Gram-negative isolates or Staphylococcus aureu s are taken as signi \201 cant. Blood samples for antigen/molecular detection New techniques allow for more rapid identi \201 cation of the presence of organisms in blood (or other body \202 uids) via molecular DNA ampli \201 ca- tion methods, e.g. PCR (polymerase chain reaction) or \202 uorescent in situ hybridisation techniques. PCR is an extremely sensitive test but is prone to envir onmental contamination (e.g. from airborne spores). It cannot distinguish between colonizat ion and infection. Urine Catheter specimens are usually obtained. The sampling site should be prepared aseptic ally. The specimen should be examined for organisms, casts, and crystals. Urine is plated o nto culture medium with a calibrated loop and incubated for 18 \200\22324h prior to examina tion. Bacteria >108/L (or a pure growth \211 105/L) are signi \201 cant. If the catheter has been in place for >2d, all urine specimens show bacterial growth. Isolation of the same organism from blood con \201 rms a signi \201 cant culture. Urine can also be used for a ntigen testing (e.g. Pneumococcus, L. pneumophilia). Sputum/bronchial samples Sputum samples are easily contaminated during collection, particul arly from non-intubated patients. Suction specimens from intubated patients can be taken vi a a sterile suction catheter, protected catheter brush, or from speci \201 c lung segments via a bronchoscope. Gram-negative bacteria are frequently isolated from tracheal aspirates of intubated patients; only deep suction specimens are signi \201 cant. Blood cultures sh ould accompany sputum specimens if pneumonia is suspected. Pus samples and wound swabs Aspirated pus must be sent to the lab immediately, or a swab ta ken and sent in transportation medium. Pus is preferable for bacterial isolation. BACTERIOLOGY 225 Typical ICU-acquired infections Pneumonia Ps. aeruginosa, S. aureus, Klebsiella spp., Enterobacter spp. Urinary infection E. coli, Ps. aeruginosa, Klebsiella spp., Proteus spp. Catheter-related sepsis S. aureus, coagulase-negative Staphylococci See also: Pleural aspiration, p86; Fibreoptic bronchoscopy, p88; Chest physiotherapy, p90; Virology, serology and assays, p226; Urinalysis, p232; Acute chest infection (1), p356; Acu te chest infection (2), p358; Infection \200\224diagnosis, p552. 226 CHAPTER 11 Laboratory monitoring Virology, serology, and assays Antibiotic assays Antibiotic assays are usually performed fo r drugs with a narrow thera- peutic range such as aminoglycosides and vancomycin. It is not usual to request an assay on day 1 of treatment. Thereafter, samples are taken daily prior to giving a dose and at 1h after an IV injection or infusion. Serology A clotted blood specimen allows antibodies to viral and atypical antigens to be as sayed. It is usual to send acute and convalescent (14 days) serum to determine rising antib ody titres. Single sample titres may be used to determine previous exposure and carrier sta tus. Hepatitis B Serology includes hepatitis B surface antigen as a screening test and hepatitis B core antigen to determine infectivity. There is a 10% carrier rate in South East Asians. Serology should be sent in all high-risk patients, e.g. jaundice, IV drug abuse, homosexua ls, prostitutes, those with tattoos or unexplained hepatic enzyme abnormalities. Serology s hould be sent in staff who suffer accidental exposure to body \202 uids, e.g. needlestick injury. Those who are not immune may be treated with immunoglobulin. HIV Since HIV positive status carries consequences for lifestyle and insurance, it should r arely be assessed without prior counseling and consent. The viral load (measure of activity ) and CD4 count may be used to assess the likelihood of symtomatology being AIDS-related, a lthough the CD4 will fall with acute critical illness; again, consent should usually be sou ght pre-testing. High-risk patients should be considered for testing, e.g. homo- sexual mal es, intravenous drug abusers, hemophiliacs, those of Central African origin. In critically ill patients, such consent can rarely be obtained and unconsented testing may be used where management may change sig- ni \201 cantly with knowledge of the HIV status or where organ donation is being considered. Most AIDS-related infections can be adequately treated witho ut knowledge of HIV status. However, patients or staff who are recipients of a needlestick injury can be treated with anti-retroviral thera- pies if the donor is known to be HIV-posi tive; unconsented testing may be reasonable in this situation. Viral culture Most commonly used for CMV. Samples of blood, urine, or bronchial aspirate ma y be sent for DEAFF (detection of early antigen \202 uorescent foci). Herpes virus infect ions may be detected by electron microscopy of samples (including pustule \202 uid) and a denovirus in immunosuppressed patients with a chest infection. Fungi Candida and Aspergillus spp. can be assessed by culture, PCR, or antigen tests. Crypt ococcus can be detected by Indian ink stain in biopsy samples. Detection in blood of galact omannan, a component of the Aspergillus cell wall is an alternative means of diagnosis. VIROLOGY, SEROLOGY, AND ASSAYS 227 Common serology for critically ill patients \200 \200 \200 \200 \200 \200 \200 Hepatitis A. Hepatitis B. Hepatitis C. HIV. CMV. Mycoplasma pneumoniae. Legionella pneumoph ilia. Antibiotic therapeutic levels Trough (mg/L) Peak (mg/L) Amikacin <8 30 Gentamicin <2 4 \200\22310* Tobramycin <2 4 \200\22310 Vancomycin <8 20 \200\22330 Seek microbiological advice if once-daily gentamicin is used See also: Bacteriology, p224; Urinalysis, p232; Acute chest infection (1), p356; Acute ches t infection (2), p358; Infection \200\224diagnosis, p552; HIV related disease, p566; SARS, VHF and H5N1, p570. 228 CHAPTER 11 Laboratory monitoring Toxicology Purpose Samples taken from blood, urine, vomitus, or gastric lavage (depending o n drug or poison ingested) for: \200 Monitoring of therapeutic drug levels (usually plasma) and avoidance of toxicity, e.g. digo xin, aminoglycosides, lithium, phenytoin, theophylline. Identi \201 cation of unknown toxi c substances (e.g. cyanide, amphetamines, opiates) causing symptomatology and/or pathology. Always take a urine sample for analysis. Con \201 rmation of toxic plasma levels and moni toring of treatment effect, e.g. paracetamol, aspirin. Medicolegal, e.g. alcohol, recreatio nal drugs following road trauma. Samples Con \201 rm with chemistry laboratory 9 local Poisons Unit as to which, how, and w hen body \202 uid samples should be taken for analysis, e.g. peak/trough levels for amino glycosides, urine samples for out-of-hospital poisoning, repeat paracetamol levels to monit or ef \201 cacy of treatment. TOXICOLOGY 229 See also: Virology, serology, and assays, p226; Poisoning \200\224general principles, p520. This page intentionally left blank 231 Chapter 12 Miscellaneous monitoring Urinalysis 232 Indirect calorimetry 234 Lactate 236 Colloid osmotic pressure 238 232 CHAPTER 12 Miscellaneous monitoring Urinalysis Techniques \200 Biochemical/metabolic: \200 Colorimetric \200\230dipsticks \200\231 read manually from reference chart or by automated machine within 15s \200\2232min of dipping in urine (see manufacturers \200\231 instructio ns). Usually performed at the bedside. Sodium and potassium levels can be measured in many analysers used for plasma electrolyte measurement. Re-calibration of the machine or special dilution techniques may be required. Laboratory analysis, e.g. for urea, osmolality, elect rolytes, creatinine, myoglobin, urate. \200 \200 Hematological \200\224either by dipstick or laboratory testing. Microbiological \200\224mic roscopy, culture, sensitivity; antigen tests. Renal disease \200\224usually by microscopy + laboratory testing. Associated tests Some of the above investigations are performed in conjunction with a blood test, e.g. urine:plasma ratios of urea, creatinine, and osmolality to distinguish renal fr om pre-renal causes of oliguria, 24h urine collection plus plasma creatinine for creatinine clearance estimation. Cautions \200 White blood cells, proteinuria, and mixed bacterial growths are routine \201 ndings in ca theterised patients and do not necessarily indicate infection. Urinary nitrite is a useful indicator of infection. A \200\230positive \200\231 dipstick test for blood does not diffe rentiate between haematuria, haemoglobinuria, or myoglobinuria. Only conjugated bilirubin i s excreted into the urine. Urinary sodium and potassium levels are increased by diuretic us age. \200 \200 URINALYSIS 233 Urinalysis tests Biochemical/metabolic: