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: pH Glucose Ketones Protein Bilirubin Nitrite Sodium, potassium Urea, creatinine, nitrogen O smolality Speci \201 c gravity Myoglobin Drugs, poisons Dipstick Dipstick Dipstick Dipstick, laboratory Dipstick Dipstick Electrolyte analyzer, lab oratory Laboratory Laboratory Bedside gravimeter, laboratory Laboratory, positive dipstick to blood Send to Poisons Reference Laboratory Hematological: Red blood cells Hemoglobin Neutrophils Microscopy, positive dipstick to blood Laboratory, positive dipstick to blood Dipstick, lab oratory Microbiological: Bacteriuria TB Legionnaire \200\231s disease Microscopy, culture Microscopy, culture (early morning specimens) Laboratory Nephro-urological: Haematuria Granular casts Protein Sodium, potassium Malignant cells Microscopy Microscopy Laboratory Electrolyte analyzer, laboratory Cytology See also: Virology, serology, and assays, p226; Diabetic ketoacidosis, p510; Hyperosmolar d iabetic emergencies, p512. 234 CHAPTER 12 Miscellaneous monitoring Indirect calorimetry Calorimetry refers to the measurement of energy production. Direct cal or- imetry is the measurement of heat production in a sealed chamber but is impractical for critically ill patients. Indirect calorimetry measures the rate of oxidation of metabolic fuels by detecting the volume of O2 consumed and CO2 produced. The ratio of CO2 production to O2 utilization (respira- tory quotient or RQ) de \201 nes which fuels are being utilize d (see table 10.1). Knowledge of the oxygen utilization by the various fuels allows calcula tion of energy production. Carbohydrate and fat are oxidized to CO2 and water producing 15 \200\22317 and 38 \200\22339kJ/g, respectively. Protein is oxidized to CO2, water, and nitr ogen (subsequently excreted as urea), producing 15 \200\22317kJ/g. Technique of indirect calorimetry Inspiratory and mixed expiratory gasses must be sampled. O2 concentra- tion may be measured by a fuel cell sensor or a fast response, paramag- netic sensor. CO2 is usually measured by infrared absorption. Sensors may be calibrated with ref erence to known concentrations of standard gas or by burning a pure fuel with a predictable O2 consumption. Measurements are usually made at ambient temperature, pressure, and humidi ty prior to conversion to standard temperature, pressure, and humidity. To calculate metabo lic rate (energy expenditure), inspired and expired minute volumes are required. It is comm on for one minute volume to be measured and the other derived from a Haldane transformation : N E N I = \227 V I V E The nitrogen concentrations are assumed to be the concentration of gas which is not O2 or C O2. Calculation of energy expenditure utilizes a mod- i \201 cation of the de Weir formula : Energy expenditure = (3.94VO2 + 1.11VCO2) \227 1.44 Although it is possible to calculate the rate of protein metabolism by reference to the uri nary urea concentration, and therefore, to separate non-protein from protein energy expendi ture, the resulting modi \201 cation of the above formula is not usually clinically signi \201 cant. Errors associated with indirect calorimetry Underestimate VCO2 H+ ion loss, haemodialysis, haemo \201 ltration. Overestimate VCO2 Hyperventilation, HCO3 Underestimate VO2 FIO2 >0.6 Loss of volume \200\223 infusion. Free radical production, unmeasured O2 supply. Small difference between inspired and expire d O2. Circuit leaks, bronchopleural \201 stula. Use of indirect calorimetry Helps to match nutritional intake to energy expenditure. It is important to feed critically ill patients appropriately, avoiding both underfeeding and ove rfeeding (see table opposite). Indirect calorimetry may also be used to assess work of brea thing by assessing the change in VO2 during weaning from mechanical ventilation. The VO2 ch ange may also be used to assess appropriate levels of sedation and analgesia. INDIRECT CALORIMETRY 235 Respiratory quotients for various metaboliic fuels Ketones Fat Protein Carbohydrate 0.63 0.71 0.80 1.00 The whole body RQ depends on the fuel or combination of fuels being utilized. Normally, a c ombination of fat and carbohydrate are utilized with an RQ of 0.8. Lipogenesis associated w ith both sepsis and overfeeding may give a RQ of 1.1 \200\2231.3. See also: Nutrition \200\224use and indications, p126; Enteral nutrition, p128; Parenteral nutrition, p130. 236 CHAPTER 12 Miscellaneous monitoring Lactate Pyruvate, the end-product of glycolysis, is taken up from the cytosol into the mito chondria by pyruvate dehydrogenase and metabolized to acetyl CoA, the entry point into the Krebs \200\231s cycle (see \201 gure 12.1). Electrons are donated from the Krebs \200\231 s cycle to the electron transportation chain via NADH and FADH2. Pyruvate not taken up by m itochondria goes into equilibrium with lactate. This reaction is catalyzed in either direct ion by lactate dehy- drogenase (see \201 gure 12.2) Causes of lactic acidosis Increased lactate production is not due simply to tissue hypoxia. It can be generated either by excess glycolysis in relation to downstream require- ments ( e.g. excess stimulation by exogenous or endogenous epinephrine) or by a downstream block, e .g. of pyruvate dehydrogenase (sepsis), oxygen insuf \201 ciency (any cause of tissue hypo xia), or mitochondrial electron transportation chain dysfunction (e.g. sepsis, CO poisoinin g). In sepsis, blood lactate levels rise in part due to increased activity of the skeletal muscle Na+ pump driven by epinephrine-stimulated glycolysis. A further cause of hyperlactataemia is decreased utilization. This is par- ticularly appare nt with liver (9 kidney) dysfunction, especially when exog- enous lactate is being administ ered, e.g. lactate-buffered renal replacement \202 uid. Lactate is a buffer, not an acid, so a high blood lactate is not, there- fore, synonymous with lactic acidosis; there needs to be a concurrent metabolic acidosis for diagnosis. Lactic acidosis is traditionally classi \201 ed as type A or type B. Type A refers to exce ss production when tissue oxygenation is inadequate. Type B occurs where there is no system ic tissue hypoxia. A severe and persistent type A lactic acidosis is associated with a poor outcome. Measurement of blood lactate Analysers are available to allow rapid measurement of blood or plasma lactate on small samples using enzyme-based methods. The enzymatic con- version of lactate to pyruvate is an oxygen-utilizing reaction. The extrac- tion of oxygen from the sa mple can be detected by a sensitive oxygen fuel cell sensor and is directly proportional to the sample lactate concentra- tion. A whole blood sample (venous or arterial since there i s no practical difference) is collected into a heparin \202 uoride tube to prevent coagul ation and glycolysis (lactate-producing). Nitrite may be used in the sample tube to convert hemoglobin to the met-form, thus avoiding uptake of oxygen during the enzyme reaction. The enzymatic method is speci \201 c for the L-isomer and will not detect D-lactate (seen, for example, in short bowel syndrome). Lactate may also be measured from regional sites to aid assessment of regional perfusion (e.g. arterial jugular venous bulb difference). Normal blood lactate <1.8mmol/L. LACTATE 237 glucose S I S Y L O C Y L G 2ATP lactate pyruvate acetyl CoA H2O Krebs \200\231s cycle O2 e \210\222 electron transportation chain 26-29ATP 2ATP Fig. 12.1 Bioenergetic pathway from oxidation of glucose. lactate dehydrogenase \210\222 \210\222 COO COO \210\222 + NADH + H+ + NAD+ C=O HOH COO \210\222 COO CH3 lactate pyruvate Fig. 12.2 Pyruvate \200\223lactate equilibrium. LIVER MUSCLE BLOOD glucose glucose 2ATP 6ATP 2 pyruvate 2 pyruvate 2 lactate 2 lactate Fig. 12.3 Cori cycle (lactate \200\223glucose between liver and muscle). Key papers Levy B, Gibot S, Franck P, et al. (2005) Relation between muscle Na+K+ ATPase ac tivity and raised lactate concentrations in septic shock: a prospective study. Lancet 365: 871 \200\2235. Totaro RJ, Raper RF. (1997) Epinephrine-induced lactic acidosis following cardiopulmonary b ypass. Crit Care Med 25:1693 \200\2239. See also: Blood gas analysis, p154; Jugular venous bulb saturation, p202; Other neurologica l monitoring, p206; Metabolic acidosis, p502. 238 CHAPTER 12 Miscellaneous monitoring Colloid osmotic pressure Colloid osmotic pressure (COP) is the pressure required to prevent net \202 uid movement between two solutions separated by a selectively per- meable membr ane when one contains a greater colloid concentration than the other. The selectively perme able membrane should impede the passage of colloid molecules, but not small ions and water. COP is deter- mined by number of molecules rather than type. However, most solu- tions exh ibit non-ideal behavior due to intermolecular interactions and electrostatic effects. Hence , COP cannot be inferred from plasma protein concentrations; it must be measured. Measurement of COP In a membrane oncometer, the plasma sample is separated from a reference 0.9% saline solution by a membrane with a molecular weight exclusion between 10,000 and 30 ,000 dalton. The reference solution is in a closed chamber containing a pressure transducer . Saline will pass to the sample chamber by colloid osmosis, creating a negative pressure i n the reference chamber. When the negative pressure prevents any further \202 ow across t he membrane, it is equal to the COP of the sample. Normal plasma COP is 25 \200\22330mmHg. Clinical use of COP measurement Assessing signi \201 cance of reduced plasma proteins Plas ma albumin levels are almost invariably reduced in critically ill patients. Causes include interstitial leakage, failed synthesis, and increased metabolism. However, the same group o f patients often has raised levels of acute phase proteins which contribute to COP. Since t here is no evidence that correc- tion of plasma albumin levels is bene \201 cial, many cli nicians correct plasma volume de \201 cit with arti \201 cial colloid. These will contrib ute to COP while also reducing hepatic albumin synthesis. If COP is maintained >20mmHg, it is likely that reduced plasma albumin levels are of no signi \201 cance. Avoiding pulmonary oedema It has been suggested that a difference between COP and pulmonary artery wedge pressure >6mmHg minimizes the risk of pulmonary oedema. However, in the face of severe capillary leak, it is unlikely that pulmonary oedema can be avoided if plasma vol umes are to be maintained compat- ible with circulatory adequacy. Conversely, a normal COP would not necessarily prevent pulmonary oedema in severe capillary leak; the contri- bution of COP to \202 uid dynamics in this situation is much reduced. Selection of appropriate \202 uid therapy It is dif \201 cult not to support the use of colloid \202 uids in hypo-oncotic patients. In patients with renal failure, the repeated use of colloid \202 uid may lead to a hyper-oncotic state. This is associated with tissue dehydra- tion and failure of glomerular \201 ltration (thus prolonging the renal failure ). Measurement of a high COP in patients who have been treated with arti- \201 cial collo ids should direct the use of crystalloid \202 uids. It is important to note that excessiv e diuresis may also lead to a hyper-oncotic state for which crystalloid replacement may be necessary. COLLOID OSMOTIC PRESSURE 239 See also: Colloids, p246. This page intentionally left blank 241 Chapter 13 Fluids Crystalloids 242 Sodium bicarbonate 244 Colloids 246 Blood transfusion 248 Blood products 2 50 CHAPTER 13 Fluids 242 Crystalloids Types \200 \200 \200 \200 Balanced electrolyte: e.g. Ringer \200\231s lactate, Hartmann \200\231s solution. Saline: e .g. 0.9% saline, 0.18% saline in 4% glucose. Glucose: e.g. 5%, 10%, 20%, 50%. Sodium bicarb onate: e.g. 1.26%, 8.4%. Uses \200 Crystalloid \202 uids to provide daily requirements of water and electrolytes. They shoul d be given to critically ill patients as a continuous background infusion to supplement \202 uids given during feeding or to carry drugs. Higher concentration glucose infusions ma y be used to prevent hypoglycaemia. Crystalloid \202 uids may contain potassum chloride s upplements. Sodium bicarbonate may be used to correct metabolic acidosis, for urinary alkal inisation, etc. \200 Routes \200 IV. Notes \200 Signi \201 cant plasma volume de \201 cit should be replaced with colloid solutions since crystalloids are rapidly lost from the plasma, particularly during periods of increased ca pillary leak, e.g. sepsis. As most plasma substitutes are carried in saline solutions, any additional salt containing crystalloid infusion is only needed to replace excess sodium los ses. The sodium content of 0.9% saline is equivalent to that of extracellular \202 uid. T herefore, salt-containing solutions distribute throughout the extracellular \202 uid spac e. Ringer \200\231s lactate or Hartmann \200\231s solution avoid hyperchloraemic acidosis c aused by the relative excess chloride infused with 0.9% saline. Hyperchloraemic acidosis ma y adversely affect coagulation and renal function though human data are lacking. A daily re quirement of 70 \200\22380mmol sodium is normal although there may be excess loss in sweat and from the gastrointestinal tract. This can be provided as saline or balanced electrolyte solution. 5% glucose is used to supply intravenous water requirements. Since there are no electrolytes to favor distribution to one space or another, water distributes uniformly thr oughout the extracellular and intracellular spaces. The 50g/L glucose content ensures an is otonic solution, but only provides 200Cal/L. Normal requirement is approximately 1.5 \200 \2232L/d. Water loss in excess of electrolytes is uncommon but occurs in excess sweating, f ever, hyperthyroidism, diabetes insipidus, and hypercalcaemia. 5% glucose is an appropriate replacement \202 uid for water loss. Potassium chloride must be given slowly since rapid injection may cause fatal arrhythmias. No more than 40mmol/h should be given and even this may be dangerous in some patients. Up to20mmol/h is safer. The frequency of infusion is di ctated by plasma potassium measurements. CRYSTALLOIDS 243 Ion content of crystalloids (mmol/L) Na+ 150 K+ Cl \200\223 150 Ca2+ \200\223 HCO3 0.9% saline Hartmann \200\231s 0.18% saline in 4% glucose 131 30 5 29 111 30 2 Ion content of gastrointestinal \202 uids (mmol/L) H+ 40 \200\22360 Na+ 20 \200\22380 120 \200\223140 120 \200\223140 120 \200\223140 100 \200\223120 K+ 5 \200\22320 5 \200\22315 5 \200\22315 5 \200\22315 5 \200\22315 \200\223 Cl \200\223 HCO3 150 30 \200\22350 70 \200\223110 20 \200\22340 20 \200\22340 Gastric Biliary Pancreatic Small bowel Large bowel 100 \200\223150 80 \200\223120 40 \200\22380 90 \200\223130 90 \200\223130 See also: \200\223), p212; Sodium bicarbonate, Nutrition \200\224use and indications, p126 ; Electrolytes (Na+, K+, Cl, HCO3 p244; Colloids, p246; Electrolyte management, p482; Hypon atraemia, p486; Hypokalaemia, p490; Metabolic acidosis, p504; Hypoglycaemia, p506. CHAPTER 13 Fluids 244 Sodium bicarbonate Types \200 \200 Isotonic sodium bicarbonate 1.26%. Hypertonic sodium bicarbonate 8.4%. Uses \200 \200 Correction of metabolic acidosis. Alkalinisation of urine, e.g. for salicylate overdose, tr eatment of rhabdomyolysis. Alkalinisation of blood, e.g. for treatment of tricyclic antidep ressant overdose. Routes \200 IV. Notes \200 Isotonic (1.26%) sodium bicarbonate may be used to correct acidosis associated with renal f ailure or to induce a forced alkaline diuresis. \200\223/mL) is rarely required in The hyp ertonic (8.4%) solution (1mEq HCO3 intensive care practice to raise blood pH in severe meta bolic acidosis. Bicarbonate therapy is inappropriate when tissue hypoperfusion or necrosis is present. Administration may be indicated as either speci \201 c therapy (e.g. alkaline diuresis for salicylate overdose) or if the patient is dyspnoeic in the absence of tissue h ypoperfusion (e.g. renal failure). The PaCO2 may rise if minute volume is not increased. Bi carbonate cannot cross the cell membrane without dissociation so the increase in PaCO2 may result in intracellular acidosis and depression of myocardial cell function. A decrease in plasma ionized calcium as a result of alkalinisation may also cause a decrease in myocardia l contractility. Signi \201 cantly worse haemodynamic effects have been reported with bica rbonate compared to equimolar saline in patients with severe heart failure. Convincing huma n data that bicarbonate improves myocardial contractility or increases responsiveness to ci rculating catecholamines in severe acidosis are lacking. Acidosis secondary to myocardial d epression is related to intracellular changes that are not accurately re \202 ected by art erial blood chemistry. Excessive administration may cause hyperosmolality, hypernatraemia, hypokalaemia, and sodium overload. Bicarbonate may decrease tissue oxygen availability by a left shift of the oxyhaemoglobin dissociation curve. Sodium bicarbonate does have a place in the management of acid retention or alkali loss, e.g. chronic renal failure, renal tubul ar acidosis, \201 stulae, diarrhea. Fluid and potassium de \201 cit should be corrected \201 rst. \200 SODIUM BICARBONATE 245 Ion content of sodium bicarbonate (mmol/L) Na+ 150 1000 K+ Cl \200\223 Ca2+ \200\223 HCO3 150 1000 1.26% sodium bicarbonate 8.4% sodium bicarbonate See also: Blood gas analysis, p154; Electrolytes (Na+, K+, Cl \210\222, HCO3 Hypernatraemia , p484; Hypokalaemia, p490; Metabolic acidosis, p502. \210\222), p212; Electrolyte management, p482; 246 CHAPTER 13 Fluids Colloids Types \200 \200 \200 \200 Albumin: e.g. 4.5 \200\2235%, 20 \200\22325% human albumin solution. Dextran: e.g. 6% Dextr an 70. Gelatin: e.g. 3.5% polygeline, 4% succinylated gelatin. Hydroxyethyl starch: e.g. 6% hetastarch, 6% hexastarch, 6 and 10% pentastarch, 6% and 10% tetrastarch. Uses Replacement of plasma volume de \201 cit. \200 \200 \200 Short-term volume expansion (gelatin, dextran). Medium-term volume expansion (albumin, pent astarch, tetrastarch). Long-term volume expansion (hetastarch, hexastarch). Routes \200 IV. Side effects \200 \200 \200 \200 Dilution coagulopathy. Anaphylaxis. Interference with blood crossmatching (Dextran 70). Nep hropathy (high dose hydroxyethyl starches). Notes \200 Smaller volumes of colloid are required for resuscitation with less contribution to oedema. Maintenance of plasma colloid osmotic pressure (COP) is a useful effect not seen with crys talloids, but colloids contain no clotting factors or other plasma enzyme systems. Albumin is the main provider of COP in the plasma and has a number of other functions. There is no evidence that maintenance of plasma albumin levels, as opposed to maintenance of plasma COP with arti \201 cial plasma substitutes, is advantageous. Hyperoncotic colloids can be use d where salt restriction is necessary. This is rarely necessary as plasma volume expansion relates to weight of colloid infused rather than concentration. Arti \201 cial colloids us ed with ultra \201 ltration or diuresis are just as effective in oedema states. Polygeline is a 3.5% solution and contains calcium (6.25mmol/L). The calcium content prevents the use of the same administration set for blood transfusions. Succinylated gelatin is a 4% soluti on and does not contain calcium. Hydroxyethyl starch solutions are protected from metabolis m due to a high degree of substitution (proportion of glucose units substituted with hydrox yethyl groups \200\224DS) or a high C2:C6 ratio of carbon atoms substituted. Prolonged itch ing related to intradermal deposition, coagulopathy, and nephropathy are complications if e xcessive doses of higher molecular weight hydroxyethyl starches are used. Pentastarch and t etrastarch provide only a short-term volume expanding effects. Hydroxyethyl starches in bal anced electrolyte solutions are available. These avoid the problem of hyperchloraemic acido sis in higher doses. There is also some evidence of less coagulation disturbance. COLLOIDS 247 Unique features of albumin \200 Transportation of various molecules. \200 Free radical scavenging. \200 Binding of toxins. \200 Inhibition of platelet aggregation. Relative persistence of colloid effect Albumin Dextran 70 Succinylated gelatin Polygeline Hetastarch (high MW, high DS, low C2:C6 ratio) Hexastarch (medium MW, high DS, high C2:C6 ratio) Pentastarch (medium MW, low DS, lo w C2:C6 ratio) Tetrastarch (low MW, low DS, high C2:C6 ratio) +++ ++ ++ + ++++ ++++ ++ ++ Persistence is dependent on molecular size and protection from metabolism. High DS and high C2:C6 ratio protect hydroxyethyl starch from metabolism. All arti \201 cial colloids are polydisperse (i.e. there is a range of molecular sizes). Key papers The SAFE Study Investigators. (2004) A comparison of albumin and saline for \202 uid resuscitation in the intensive care unit. N Engl J Med 350: 2247 \200\22356. Brunkhorst F, Engel C, Bloos F, et al. (2008) Intensive insulin therapy and pentastarch res uscitation in severe sepsis. N Engl J Med 358: 125 \200\22339. See also: Colloid osmotic pressure, p238; Crystalloids, p242; Basic resuscitation, p338; Fl uid challenge, p342; Anaphylactoid reactions, p578. 248 CHAPTER 13 Fluids Blood transfusion Blood storage Blood cells are eventually destroyed by oxidant damage duri ng storage of whole blood. Since white cells and plasma enzyme systems are impor- tant in t his cellular destruction, effects are correspondingly less severe for packed red cells. Blo od used for transfusion in most of Europe is now routinely leukodepleted to prevent acute n on-haemolytic transfusion reactions. Microaggregate formation is associated with platelets, white cells, and \201 brin, and range in size from 20 \200\223170 m. The risk of microa g- gregate damage is reduced with packed cells. In addition to spherocytosis and haemolysis , prolonged storage depletes ATP and 2,3-DPG levels, thus increasing the O2 af \201 nity o f the red cells. If whole blood is to be used in critically ill patients, it should be as f resh as possible. Compatibility In an emergency with massive blood loss that threatens life, it is permis- si ble to transfuse O-negative packed cells, but a sample must be taken for grouping prior to transfusion. With modern laboratory procedures, it is possible to obtain ABO compatibility for group speci \201 c transfusion within 5 \200\22310min and a full crossmatch in 30min. Hazards of blood transfusion \200 Citrate toxicity \200\224hypocalcaemia is rarely a problem. The prophylactic use of calcium supplementation is not recommended. Potassium load \200\224potassium returns to cells rapi dly, but hyperkalaemia may be a problem if blood is stored at room temperature. Jaundice \200\224haemolysis of incompatible or old blood. Pyrexia \200\224immunological transfusion reactions to incompatible red or white cells or platelets or blood products DIC \200\224par tial activation of clotting factors and destruction of stored cells, either in old blood or when transfusion is incompatible. Anaphylactoid reaction \200\224urticaria is common and p robably due to a reaction to transfused plasma proteins; if severe, it may be treated by sl owing the transfusion and giving chlorpheniramine 10mg IV/IM. In severe anaphylaxis, in add ition to standard treatment, the transfusion should be stopped and saved for later analysis . A sample should be taken for further crossmatching. Transmission of disease \200\224inclu ding viruses, parasites (malaria), prions. Transfusion-related acute lung injury (TRALI) an d other immune reactions. A multicentre trial suggested liberal transfusion in the critical ly ill produced less favorable outcomes, particularly in younger, less sick patients, than using a trigger hemoglobin of 7g/dL. This was performed with non-leukodepleted blood; the v alidity with leukodepleted blood now in common use is uncertain. \200 \200 BLOOD TRANSFUSION 249 Key paper Hebert P, Wells G, Blajchman M, et al. for the Tranfusion Requirements in Critica l Care Investigators. (1999) A multicentre, randomized, controlled clinical trial of transf usion require- ments in critical care. N Engl J Med 340: 409 \200\22317. See also: Basic resuscitation, p338; Upper gastrointestinal hemorrhage, p412; Bleeding vari ces, p414; Lower intestinal bleeding and colitis, p420; Jaundice, p428; Anemia, p472; Sickl e cell disease, p474; Haemolysis, p476; Hyperkalaemia, p488; Anaphylactoid reactions, p578. 250 CHAPTER 13 Fluids Blood products Types \200 \200 \200 Plasma, e.g. fresh frozen plasma. Platelets. Concentrates of coagulation factors, e.g. cryo precipitate, factor VIII concentrate, factor IX complex, Octaplex. Recombinant technologies , e.g. factor VIIa, factor VIII. Uses \200 Vitamin K de \201 ciency (fresh frozen plasma, factor IX complex, Octaplex). Hemophilia (c ryoprecipitate, factor VIII, recombinant factor VIIa). von Willebrand \200\231s disease (cr yoprecipitate). Fibrinogen de \201 ciency (cryoprecipitate). Christmas disease (factor IX complex). \200 \200 \200 Routes \200 IV. Notes \200 A unit (150mL) of fresh frozen plasma is usually collected from one donor and contains all coagulation factors, including 200U factor VIII, 200U factor IX, and 400mg \201 brinogen. It is stored at \200\22330*C and should be infused within 2h once defrosted. Platelet con centrates are viable for three days when stored at room temperature. Viability decreases if they are refrigerated. They must be infused quickly via a short giving set with no \201 lter. Indications for platelet concentrates include platelet count <10x109 or <50x109 with spontaneous bleeding or to cover invasive procedures and spontaneous bleeding with platelet dysfunction. They are less useful in conditions associated with immune platelet destructio n (e.g. ITP). A 15mL vial of cryoprecipitate contains 100U factor VIII, 250mg \201 brinog en, factor XIII, and von Willebrand factor and is stored at \200\22330*C. In hemophilia, c ryoprecipitate is given to achieve a factor VIII level >30% of normal. Factor VIII concentr ate contains 300U factor VIII per vial. In severe hemorrhage due to hemophilia, 10 \200\223 15U/kg are given 12-hourly. Recombinant factor VIIa is indicated for control of bleeding in patients with hemophilia with inhibitors to factors VIII or IX, or congenital factor VII d e \201 ciency. It forms complexes with exposed tissue factor and is not dependent on the p resence of factors VIII or IX. It has been shown to reduce blood transfusion requirements i n major blunt trauma. Success has been reported in cases of uncontrollable intra- operative bleeding (90mcg/kg repeated every 2 \200\2233h until bleeding stops). Octaplex is a prothr ombin complex concentrate for the substitution of factors II, VII, IX, and X in treatment o r prophylaxis of hereditary and acquired coagulation factor disorders, e.g. warfarin overdo se. BLOOD PRODUCTS 251 Key paper Boffard KD, for the NovoSeven Trauma Study Group. (2005) Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two paralle l randomized, placebo- controlled, double-blind clinical trials. J Trauma 59: 8 \200\22315. See also: Plasma exchange, p114; Full blood count, p220; Coagulation monitoring, p222; Coll oids, p246; Blood transfusion, p248; Anticoagulants, p318; Bleeding disorders, p468; Clotti ng disorders, p470; Platelet disorders, p478. This page intentionally left blank 253 Chapter 14 Respiratory drugs Bronchodilators 254 Respiratory stimulants 256 Nitric oxide 258 Surfactant 260 254 CHAPTER 14 Respiratory drugs Bronchodilators Types \200 \200 \200 \200 B2 agonists, e.g. salbutamol, epinephrine, terbutaline. Anticholinergics, e.g. ipratropium. Theophyllines, e.g. aminophylline. Others, e.g. magnesium, ketamine, iso \202 urane. Uses \200 Relief of bronchospasm. Routes \200 \200 \200 Inhaled (salbutamol, epinephrine, terbutaline, ipratropium, iso \202 urane). Nebulised (sa lbutamol, epinephrine, terbutaline, ipratropium). IV (salbutamol, epinephrine, terbutaline, ipratropium, aminophylline, magnesium, ketamine). PO (aminophylline). Side effects \200 \200 CNS stimulation (salbutamol, epinephrine, terbutaline, aminophylline). Tachycardia (salbuta mol, epinephrine, terbutaline, aminophylline, ketamine). Hypotension (salbutamol, terbutali ne, aminophylline, iso \202 urane). Hyperglycaemia (hydrocortisone, prednisolone, epinephr ine). Hypokalaemia (salbutamol, epinephrine, terbutaline). Lactic acidosis (salbutamol) \200\224rare. \200 \200 \200 Notes \200 Selective B2 agonists are usually given by inhalation via a pressurized aerosol or a nebuli ser. Inhalation often gives rapid relief of bronchospasm. The aerosol is of less bene \201 t in severe asthma unless used with a spacer device. They can be given by IV infusion. Neb ulised drugs require a minimum volume of 4mL and a driving gas \202 ow of 6 \200\2238L/mi n (higher or lower \202 ow creates the wrong particle size for drug delivery). In extremi s, epinephrine may be used IV, SC, or injected down the endotracheal tube. As epinephrine i s not selective, arrhythmias are more likely. However, the A agonist effect may reduce muco sal swelling by vasoconstriction, further improving air \202 ow. Ipratropium bromide does not depress mucociliary clearance, but may thicken sputum due to its anticholinergic effect . It is synergistic with B2 agonists, but has a slower onset of action. Its use in critical care is poorly studied. Aminophylline is synergistic with B2 agonists. Dosages must be adj usted according to plasma levels (range 10 \200\22320mg/L) since toxic effects may be sever e. Dose requirements are lower with heart failure, liver disease, chronic air \202 ow limi tation, fever, erythromycin, and higher in children, smokers, and those with a moderate to high alcohol intake. Magnesium is a useful adjunctive therapy for severe asthma. Ketamine o r iso \202 urane may be useful for sedation and bronchodilatation in the ventilated asthma tic. \200 BRONCHODILATORS 255 Drug dosages Aerosol* 100 \200\223200mcg 250 \200\223500mcg Nebuliser* 2.5 \200\2235mg 5 \200\22310mg 0.5mg 250mcg IV bolus IV infusion 3 \200\22320mcg/min Salbutamol Terbutaline Epinephrine Ipratropium Aminophylline 1.5 \200\2235mcg/min 5mg/kg over 20min 1.2 \200\2232g over 20min 1 \200\2232mg/kg 0.5mg/kg/h Magnesium Ketamine * Aerosols and nebulisers are usually given four to six times daily, but may be gi ven more frequently if necessary. <0.75mg/kg/h In extremis, epinephrine may be given as 0.1 \200\2230.5mg subcutaneously, injected down th e endotracheal tube or by IV infusion. See also: Chest physiotherapy, p90; Pulmonary function tests, p148; Corticosteroids, p328; Chronic air \202 ow limitation, p354; Acute chest infection (1), p356; Asthma \200\224gene ral management, p364. 256 CHAPTER 14 Respiratory drugs Respiratory stimulants Types \200 \200 Drug antagonists, e.g. naloxone, \202 umazenil. CNS stimulants, e.g. doxapram. Uses \200 \200 Acute respiratory failure due to failure of ventilatory drive. Drug-induced ventilatory fai lure, e.g. as a result of excessive sedation or post-operatively. Routes \200 IV. Modes of action \200 \200 \200 Naloxone \200\224short-acting opiate antagonist. Flumazenil \200\224short-acting benzodiaze pine antagonist. Doxapram \200\224generalized central nervous system stimulant with predomi nant respiratory stimulation at lower doses. Stimulation of carotid chemoreceptors at very low doses with increased tidal volumes. Side effects \200 \200 \200 Seizures ( \202 umazenil, doxapram). Tachyarrhythmias (naloxone, \202 umazenil). Halluci nations (doxapram). Notes \200 