Decreased oxygenation \200 \200 Decreased oxy-Hb binding Decreased 2,3-DPG (late) Further reading Androgue H, Madias N. Management of life-threatening acid \200\223base disorders. First of two parts. N Engl J Med 1998; 338: 26 \200\22334. Androgue H, Madias N. Management of life-threatening acid-base disorders. Second of two par ts. N Engl J Med 1998; 338: 107 \200\22311. Kellum J. Closing the gap on unmeasured anions. Critical Care. 2003; 7: 219 \200\22320. Kellum J. Determinants of blood pH in health and disease. Critical Care. 2000; 4: 6 \200\22314. Kellum J, Song M, Li J. Science review: extracellular acidosis and the immune response: cli nical and physiological implications. Crit Care 2004; 8: 331 \200\2236. Schlichtig R, Grogono AW, Severinghaus JW. Human PaCO2 and standard base excess compensatio n for acid-base imbalance. Crit Care Med 1998; 26: 1173 \200\2239. Wooten EW. Science review: quantitative acid \200\223base physiology using the Stewart model. Crit Care 2004; 8: 448 \200\22352. 420 R MURUGAN & JA KELLUM Metabolic acidosis etiology Ketoacidosis Ketones are formed by B-oxidation of fatty acids, a process inhibited by insul in. In insulin-de \201 cient states (e.g. diabetes), ketogenesis is accelerated due to hig h glucose-induced osmotic diuresis which may lead to volume contraction. This state is asso ciated with elevated cortisol and catecho- lamine secretion, which further stimulates free fatty acid production. In addition, increased glucagon, relative to insu- lin, leads to dec reased malonyl co-enzyme A and increased carnitine palmityl acyltransferase, the combinatio n of which increases ketogenesis. Ketone bodies include acetone, acetoacetate and B-hydroxy butyrate. Both acetoacetate and B-hydroxybutyrate are strong anions that decrease the SID a nd increase the H+ concentration. Ketoacidosis may result from diabetes (DKA) or alcohol (A KA). Pure metabolic acidosis is characterized by \200 \200 \200 \200 Acidaemia (arterial pH <7.35) Hypobicarbonatqemia (HCO3 Hypocarbia (PCO2 <40mm Hg) and a De creased SBE (less than \200\2233mEq/l) \200\223 <22 mmol/l) Metabolic acidoses are categorized according to the pres- ence or absence of unmeasured ani ons \200\224which are rou- tinely detected by examining the plasma electrolytes and calcula ting the AG. Metabolic acidosis with an increased AG Lactic acidosis During critical illness, lactate is the most important cause of metabolic acidosis and correlates with outcome in patients wit h haemorrhagic and septic shock. The assumption that hypoperfusion is the most likely cause has been seriously challenged, especially in well resuscitated patients. The aeti- ology o f hyperlactataemia during critical illness is complex, multi-factorial and arises due to se veral mechanisms (Table 24.5.1). Lactate is released from the mesentry during gut ischaemia and from the lungs during ALI. Hyperlactataemia in sepsis usually occurs as a consequence of increased aero- bic metabolism rather than tissue hypoxia. Lactate produc- tion alters c ytosolic, and hence mitochondrial redox state such that the increased NADH/NAD supports oxi dative phosphorylation as the dominant source of ATP produc- tion. Catecholamines, especial ly epinephrine, result in lactic acidosis presumably by stimulating cellular metabolism (e. g. increased hepatic glycolysis and muscle Na+,K+ ATPase) and is a common source of lactic acidosis in the ICU. Diagnosis \200 \200 Diagnosis is established by measuring serum ketones. Nitroprusside reaction only measures a cetone and ace- tate, but not B-hydroxybutyrate. Measured ketosis is dependent on the ratio of acetoac- etate to B-hydroxybutyrate. Ketones may even appear to increase as B-hydroxybu - tyrate is converted to acetoacetate during treatment. Treatment \200 The treatment of DKA includes insulin and large amounts of isotonic IV \202 uids Potassiu m replacement is often required Fluid resuscitation reverses the hormonal stimuli for keton e body formation and insulin allows for the metab- olism of ketones and glucose Sodium bica rbonate is rarely necessary and should prob- ably be avoided except in extreme cases Respon se to therapy is observed by monitoring pH and AG more than by the assay of serum ketones T he treatment of alcoholic ketoacidosis consists of \202 uids and glucose instead of insul in. Thiamine must also be given to avoid precipitating Wernicke s encephalopathy \200 Table 24.5.1 Mechanisms of hyperlactataemia during critical illness. Tissue hypoxia Hypodynamic shock Organ ischaemia Hypermetabolism Increased aerobic glycolysis Increased protein catabolism Hematologic malig nanciesal Renal failure Renal failure allows the build up of sulfates and other acids, thereby increa sing the AG. Uncomplicated renal failure rarely produces severe acidosis except when it is accompa- nied by high rates of acid generation such as from hyper- metabolism. In all cases , the SID is decreased and is expected to remain so unless some therapy is provided. Haemod ialysis will permit the removal of sulfate and other ions and allow normal Na+ and Cl \200 \223 balance to be restored, thus returning the SID to normal. However, patients not yet re quiring dialysis and those who are between treat- ments often require some other therapy to increase the SID. Sodium bicarbonate is used as long as the plasma Na+ concentration is no t already elevated. Other options include Ca2+ which usually requires replacement. Ca2+ rep lacement cannot increase the SID much given the rather narrow range of free Ca2+. Poisons M etabolic acidosis with an increased AG is a major feature of various types of drug and subs tance intoxications. It is important to recognize these disorders so that speci \201 c the rapy can be provided rather than to treat the acid \200\223base Decreased clearance of lactate Liver failure Shock Inhibition of pyruvate dehydrogenase Thiamine de \201 ciency Endotoxin Treatment \200 Treatment of underlying cause is the most important measure to correct lactic acidosis; how ever, this may not always be possible. Therapy aimed at increasing oxygen delivery may not always be effective. Although treatment with sodium bicarbonate and dichloroacetate (the en zyme that stimulates pyruvate dehydrogenase (PDH)) improves pH, they do not improve outcome ; nevertheless, Na-bicarbonate is used particularly when lactic acidosis is severe or refra ctory. 421 CHAPTER 24.5 Metabolic acidosis etiology Cl \200\223 and the balance of each anion can be adjusted depend- ing on the acid \200\223b ase status of the patient. If suf \201 cient amounts of weak anions are not provided, the plasma Cl \200\223 concentration will increase, decreasing the SID and result- ing in acido sis. A similar condition may arise when saline is used for \202 uid resuscitation, result ing in a so-called \200\230dilu- tional acidosis \200\231. The clinical implication for ma nagement of patients in the ICU is that when large volumes of \202 uid are used for resus citation they should be more physiological than saline. One alternative is lactated Ringer \200\231s solution. This \202 uid contains a more physiological difference between Na+ an d Cl \200\223 concentrations and thus the SID is closer to normal ( 28mEq/l compared with s aline which has a SID of 0mEq/l). disorder that they produce. The use of the osmolar gap can often detect toxins with high os molality (e.g. methanol). Unknown causes Recently, some unknown causes of an increased AG have been reported in non-k etotic hyperosmolar state of diabe- tes, sepsis, liver disease and in experimental animals given endotoxin. Also unknown cations appear in the blood of some critically ill patients; the significance of these is unknown, but increased mortality has been reported in some stu dies. Non-anion gap (hyperchloraemic) acidoses Hyperchloraemic acidosis occurs as a result of eit her an increase in Cl \200\223 relative to strong cations, especially Na+, or the loss of c ations with retention of Cl \200\223. When acidosis occurs, the normal response by the kidn ey is to increase Cl \200\223 excretion. Failure to do so identi \201 es the kidney as the source of acidosis. Extrarenal hyperchloraemic acidoses occur as a result of exogenous Cl \200\223 loads (iatrogenic acido- sis \200\224aline) or because cations are lost from the l ower GI tract without proportional loss of Cl \200\223. Renal tubular acidosis Examination of the urine and plasma electrolytes and pH, and calculation of the urine SIDa allows one t o diagnose most cases of renal tubular acidosis correctly. However, caution must be exercis ed when the plasma pH is >7.35 because this may turn off urine Cl \200\223 excretion. In su ch cir- cumstances, it may be necessary to infuse sodium sulfate or furosemide. These agent s stimulate Cl \200\223 and K+ excre- tion, and may be used to unmask the defect and to pro be K+ secretory capacity. The defect in all types of renal tubu- lar acidosis is the inabil ity to excrete Cl \200\223 in proportion to Na+, although the reasons vary by type. Treatme nt is largely dependent on whether the kidney will respond to miner- alocorticoid replaceme nt or whether there is loss of Na+ that can be replaced as sodium bicarbonate. Unexplained hyperchloraemic acidosis Critically ill patients sometimes manifest hyperchlora emic metabolic acidosis for unclear reasons. Often these patients have other co-existing ty pes of metabolic acidosis, making the precise diagnosis dif \201 cult. For example, some p atients with lactic acidosis have more acidosis than can be explained by the increase in la ctate concentration, and patients with sepsis and acidosis frequently have normal lactate l evels. Often, unexplained anions are the cause, but also quite often there is a hyperchlora emic acidosis. Experimental evidence in endotoxemic animals suggests that as much as a thir d of the acidosis is still unexplained. A potential explanation for this \201 nding is th e partial loss of Donnan equilibrium between plasma and interstitial \202 uid. The severe , accompanying, capillary leak results in loss of albumin from the vascular space, necessit ating the move- ment of another ion to maintain charge balance between the two compartments . If Cl \200\223 moves into the plasma space to restore charge balance, a strong anion woul d be replac- ing a weak anion and a hyperchloraemic metabolic acidosis would result. Further reading Alberti KGMM. Diabetic emergencies. BMJ 1989; 45: 242 \200\22363. Cooper DJ , Walley KR, Wiggs BR, et al. Bicarbonate does not improve hemodynamics in critically ill p atients who have lactic acidosis: a prospective, controlled clinical study. Ann Intern Med 1990; 112: 492 \200\2238. Gastrointestinal acidosis Diarrhea signi \201 cant enough to produce a hyperchlorae- mic m etabolic acidosis is usually dif \201 cult to miss. Fluid secreted into the gut lumen cont ains higher amounts of Na+ than Cl \200\223, similar to the differences in plasma. Extremel y large losses of these \202 uids, particularly if volume is replaced with \202 uids co ntaining equal amounts of Na+ and Cl \200\223, will result in a decrease in the plasma Na+ concentration rela- tive to the Cl \200\223 concentration and a decrease in the SID. Such a scenario can be avoided if solutions such as lactated Ringer \200\231s are used instead of water or saline. Ringer \200\231s solu- tion has a more physiological SID and therefore do es not produce acidosis except in rare circumstances. Gore DC, Jahoor F, Hibbert JM, et al. Lactic acidosis during sepsis is related to increased pyruvate production, not de \201 cits in tissue oxygen availability. Ann Surg 1996; 224: 97 \200\223102. Kellum JA. Determinants of blood pH in health and disease. Crit Care 2000; 4: 6 \200\22314. Kellum JA, Kramer DJ, Lee KH, et al. Release of lactate by the lung in acute lung injury. Chest 1997;111: 1301 \200\2235. Stewart PA. Modern quantitative acid \200\223base chemistry. Can J Physiol Pharmacol 1983; 61: 1444 \200\22361. Iatrogenic acidosis Two of the most common causes of a hyperchloraemic metabolic acidosis a re iatrogenic, and both are due to administration of chloride. Modern parenteral nutrition formulas contain weak anions such as acetate in addition to Weil MH, A \201 \201 AA. Experimental and clinical studies on lacate and pyruvate as ind icators of the severity of acute circulatory failure (shock). Circulation 1970; 41: 989 \200\2231001. 422 MA BUTKUS, N MADDEN, & JA KELLUM Metabolic alkalosis Clinical features Metabolic alkalosis usually manifests by: \200 \200 \200 The normal range of blood pH is between 7.35 and 7.45, with >7.45 indicating alkalaemia. Wh en alkalaemia is a result of loss of volatile acids such as CO2 it is classi \201 ed as a respiratory alkalosis, while alkalaemia arising from non- CO2 causes (e.g. strong ion imbal ances) is classi \201 ed as metabolic alkalosis. Metabolic alkaloses follow the same physi cal \200\223chemical principles as metabolic acidoses (see Chapter 24,4). In broad terms, m etabolic alkalosis can result as a conse- quence of an inappropriately large strong ion dif ference (SID). SID may be increased by the loss of anions in excess of cations (e.g. vomiti ng, diuretics) or, rarely, by administra- tion of strong cations in excess of strong anions (e.g. Na+ together with a metabolizable anion such as citrate, bicar- bonate, lactate or a cetate). Metabolic alkaloses can be divided into two broad catego- ries: chloride-responsiv e and chloride-resistant. The urine Cl \200\223 concentration can be used to help narrow th e differen- tial diagnosis. In chloride-responsive metabolic alkalosis, Cl \200\223 losses in excess of Na+ increase the SID. Chloride- resistant alkalosis results in a urine Cl \200 \223 concentration >20mmol/l and is usually caused by mineralocorticoid excess or active di uretic use. Alkalaemia (arterial pH >7.45) Hyperbicarbonataemia (HCO3 Hypercarbia (PCO2 >40mm Hg) and a n increased SBE (>3mEq/l). Urine chloride: \200 \200 \200\223 >26mmol/l) Cl-responsive: urine chloride <10mmol/l Cl-resistant: urine chloride >20mmol/l Assessment of metabolic alkalosis should include examina- tion of the extracellular \202 uid volume, including, recum- bent/upright blood pressure, skin turgor, capillary re \201 ll, and CVP measurement to assess volume status. Symptoms and signs Metabolic alkalosis causes changes in central and periph- eral nervous s ystem function (e.g. confusion, obtundation, seizures, paraesthesias, etc.) muscular crampi ng and/or tetany, arrhythmias and hypoxemia. A family history may reveal an underlying caus e associated with a mineralocor- ticoid excess (e.g. Cushing \200\231s or Liddle \200\231s syndrome). In these instances, acute metabolic alkalosis is generally ruled out and the att ention should turn to chronic alkalosis. Epidemiology Metabolic alkaloses frequently occur as sequelae to other acute and chronic co nditions; the incidence and prevalence will vary dependent upon the underlying etiology of the metabolic disorder. Acute metabolic alkaloses are more frequent than chronic alkaloses. Management Serum electrolytes, ABG values and urine chloride should be reviewed. There may be a concomitant respiratory component involved, and the expected arterial pCO2 value assoc iated with metabolic alkalosis should be calculated by \200\223 concentration or the SBE. using the HCO3 Causes There are four mechanisms that result in increases in SID and consequent metabolic a lkalosis: 1 Severe depletion in free water induces a parallel increase in Na+ and Cl \200 \223. The relative plasma concentration of Na+ becomes greater than that of Cl \200\223, in creasing the SID. 2 Any disorder that leads to Cl \200\223 loss from the GI tract or urine \200\223) + 21 or, pCO2 = (0.7 x HCO3 pCO2 = 40 + (0.6 x SBE) A measured pCO2 value >2mm Hg more than the derived expected value indicates respiratory ac idosis while a pCO2 value <2mm Hg indicates respiratory alkalosis. Treatment Treat the underlying etiology. The recognition of the dis- order and the subseque nt differential diagnosis (chloride- responsive or chloride-resistant) are essential \201 rst steps. Based on the etiology, attention should be given to the reversal of Cl \200\223 depletion, volume restoration and prevent- ing additional losses. in excess of Na+. Common causes include: \200 \200 \200 \200 Diuretic use (or abuse) Vomiting or gastric drainage Chloride-wasting diarrhea (villous ade noma) Chronic respiratory failure and elevated pCO2 (post- hypercapnic metabolic alkalosis caused by compensa- tory renal Cl \200\223 loss). All forms of mineralocorticoid excess can produce renal Cl \200\223 wasting and chronic metabolic alkalosis: pri- mary hyperaldoster onism (Conn \200\231s syndrome), sec- ondary hyperaldosteronism, Cushing \200\231s syndrome , Liddle \200\231s syndrome, Bartter \200\231s syndrome, exogenous corticoids and excessive liquorice intake. Chloride-responsive alkalosis: \200 Diuretic-induced metabolic alkalosis is the most common acute metabolic alkalosis. Saline s hould be administered in this instance. A 0.45% saline solution is effective at reversing t he free water de \201 cit and relative chloride depletion (this solution will actually red uce the [Cl \200\223] but, since it reduces [Na+] more, SID will fall. Several litres may b e required throughout the \201 rst days of treatment. If hypokalaemia is present with vol ume depletion, 20 \200\22340mEq/l of KCl can be added to 0.45% saline or given separately. Additionally, diuretics should be discontinued. In patients with underlying renal failure o r risk for vol- ume overload, 0.1M HCl (100mmol Cl \200\223/l) can be admin- istered with c aution via a central venous line to treat the Cl \200\223 depletion. A repeat evaluation of the metabolic alka- losis is recommended after each liter is infused. 3 Na+ administration in excess of Cl \200\223. Administration of non-chloride sodium salts can occur via: \200 \200 \200 \200 \200 Massive blood transfusions (sodium citrate) Parenteral nutrition (sodium acetate) Plasma vo lume expanders (acetate or citrate) Ringer \200\231s solution (sodium lactate) Overzealous use of sodium bicarbonate 4 A severe de \201 ciency of intracellular cations such as magne- sium or potassium. This de \201 ciency primarily decreases intracellular Cl \200\223 and secondarily reduces total body Cl \200\223; this results in an increased net SID. 423 CHAPTER 24.6 Metabolic alkalosis In patients actively losing gastric \202 uid, H2-blockers and/or PPIs are useful in treat ment as they reduce gastric Cl \200\223 loss. If severe, additional interventions such as R RT may be required. Renal failure and acetazolamide-resistant vol- ume overload are common indications for dialysis. Peritoneal dialysis should use normal saline with electro- lyte c oncentrations as indicated. Haemodialysis should \200\223 concentrations for the dia- inco rporate low HCO3 lysate. Table 24.6.1 Common causes of metabolic alkalosis Chloride responsive: Gastric losses (e.g. vomiting, mechanical drainage, bulimia) Post-chloruretic diuretic use (e.g. bumetanide, chlorothiazide, metolazone, etc.) Diarrhoeal states (e.g. villous adenoma, congenital chloridorrhoea) Post-hypercapneic state Chloride-resistant alkalosis: Cases of chloride-resistant metabolic alkalosis are most comm only seen in the chronic state, but can occur acutely (e.g. glycyrrhizic acid). Aetiologies involving hypoka- laemia and hypomagnesaemia warrant the appropriate electrolyte repletion . Glycyrrhizic acid-induced alkalosis is usually self-correcting upon the discontinuation o f inges- tion. K+-sparing diuretics may also be given if there is no improvement. Hypoalbum inemic alkalosis In theory, a reduction in weak acids (typically albumin) will induce metab olic alkalosis. However, hypoalbuminae- mia results in a decreased SID (principally through renal Cl \200\223 excretion. Thus, a \200\230normal \200\235 \200\231 SID in the face of hypoalbu- minaemia is in fact abnormally high. Acute hypoalbuminae- mia would result in acu te alkalosis until renal compensation can occur but, in practice, acute hypoalbuminaemia is almost always due to crystalloid resuscitation and the resulting pH is a function of both the dilution of albumin and changes in SID (see Chapter 24.5). Gastrocystoplasty Cystic \201 brosis Post-organic acidosis Milk-alkali syndrome Select antibiotics (e.g. carbenicillin, gentamicin, penicillin, ticarcillin) Sodium bicarbonate loading Excess cation administration: Sodium salt administration (acetate, citrate) Blood transfusions Plasma volume expanders Sodium lactate Parenteral nutrition Chloride resistant: Mineralcorticoid excess Excessive licorice consumption (glycyrrhizic acid and carbenoxolone) Complications Alkalosis may be less well tolerated than acidosis since relatively mild incr eases in arterial pH may cause adverse clinical effects, especially if the alkalaemia devel oped rap- idly (e.g. seizures and respiratory depression may occur when arterial pH is brou ght to 7.60). \200 Bartter syndrome Cushing syndrome Liddle syndrome Gitelman syndrome Hyperaldosteronism (primary and secondary) Alkalosis affects tissue oxygenation by decreasing the tendency of hemoglobin to release ox ygen in tissue capillaries. Concomitant with these shifts, intracel- lular alkalosis can in crease oxygen demand by stimulat- ing glycolysis. Increased oxygen demand coupled with decr eased oxygen delivery exacerbates tissue hypoxia. Alkaloses can produce ion de \201 cienci es and excess (e.g. hypokalaemia, hypophosphataemia, hypercarbia, hyper- bicarbonataemia, e tc.), which increase the risk of mor- bidity and mortality. These abnormalities can alter n euromuscular excitability and coronary blood \202 ow, produce seizures, impair enzymatic function, alter car- diac inotropy, increase the accumulation of organic acids and exacerba te drug toxicity (e.g. digoxin). Compensatory hypoventilation resulting in increased pCO2 c an result in CNS depression and pulmonary hypertension. The consequences of decreased level s of oxygen delivery throughout the system can, in cases of severe alkalosis, be quite seri ous (pH >7.60). The cardiovascular response to metabolic alkalosis is primarily vasoconstri ction and a subsequent decrease in coronary blood \202 ow. Transient increased cardiac in ot- ropy may result. In some instances, cardiac arrhythmias may be detectable. Neurological ly, metabolic alkalosis may induce delirium, apathy, neuromuscular excitability or, in more severe instances, seizures. Antineoplastic drugs (e.g. cisplatin) Miscellaneous (unknown aetiologies or able to result in resistant and responsive alkalosis) : Prolonged diuretic usage Prolonged laxative usage Ion imbalances: Hypoalbuminaemia Hypophosphataemia Hypokalaemia Hypomagnesaemia Metabolic alkalosis in the presence of volume overload (e.g. in the presence of congestive heart failure) is best treated with potassium chloride solutions. If diuresis is necessary, K+-sparing diuretics (e.g. spironolactone), which also spare Cl \200\223 concentrations, c an be used in therapy. Alternatively, in persons with adequate renal function, a carbonic a nhydrase inhibitor such as aceta- zolamide can be administered at a rate of 250 \200\223500 mg bid. Acetazolamide is associated with Na+ excretion in excess of Cl \200\223 excretion, thus a net increase in SID. Acetazolamide also increases K+ secretion, making it useful if K+ is elevated. Complications of acetazolamide use are hypokalaemia and metabolic acidosis. 424 MA BUTKUS, N MADDEN, & JA KELLUM Further reading Kaplan LJ, Frangos S. Clinical review: acid \200\223base abnormalities in t he Morgan TJ. Clinical review: the meaning of acid \200\223base abnormalities in the intensive care unit \200\224effects of \202 uid administration. Crit Care 2005; 9: 204 \200\22311. intensive care unit. Crit Care 2005; 9: 198 \200\223203. Neligan PJ, Deutschmann CS. Acid \200\223base balance in critical care Kellum JA. Clinical review: reuni \201 cation of acid \200\223base physiology. medicine. Contemp Crit Care 2004; 216: 1 \200\2239. Crit Care 2005; 9: 500 \200\2237. Stewart P. Modern quantitative acid \200\223base chemistry. Can J Physiol Kellum JA. Diagnosis and treatment of acid \200\223base disorders. Textbook of critical car e medicine. Philadelphia: Elsevier, 2005. Pharmacol 1983; 61: 1444 \200\22361. This page intentionally left blank 426 L LANGOUCHE, I VANHOREBEEK, & G VAN DEN BERGHE Glycaemic control in the critically ill Potential risks Multi-variate logistic regression analysis of the surgical study indicated that blood glucose control rather than the insulin dose administered statistically explains most of the bene \201 cial effects of tight glycaemic control. The risk of death was line arly correlated with the degree of hypergly- caemia. A reduction of blood glucose levels to <6.1mmol/l appeared to be crucial to gain most bene \201 t on mortality and for the preve ntion of events that cause morbidity. Hyperglycaemia is common in acute illnesses, irrespective of diabetic status. Moderate hype rglycaemia has been con- sidered bene \201 cial, ensuring adequate glucose as an energy so urce for organs that do not require insulin for glucose uptake \200\224the brain and the im mune system. However, even a moderate hyperglycaemia is related to adverse outcome as has b een shown in a study on tight glycaemic control in the critically ill. Clinical studies In a surgical ICU, tight glycaemic control had bene \201 cial effects on both mortality and morbidity. Comparison was made between conventional insulin use with a m ean blood glucose of 8.3 \200\2239.9mmol/l and intensive insulin therapy, with blood glucos e levels between 4.4 and 6.1mmol/l (mean blood glucose levels of 5.0 \200\2235.5mmol/l). In 2006, the effects of tight glycaemic control in the medical ICU showed that tight glycaemi c control significantly reduced morbidity, (mortality reduction did not reach statistical s igni \201 cance). In long-stay patients, maintaining normoglycaemia significantly reduced mortality and morbidity. Effects of tight glycaemic control in the critically ill were: \200 \200 \200 Controversy The prospective VISEP trial \200\224the insulin arm of the study \200\224 was s topped prematurely because the rate of hypoglycae- mia in the intensive treatment group was considered unacceptably high (12.1%). The GLUCONTROL study to assess whether tight glycaem ic control (4.4 \200\2236.1mmol/l) improves survival in a mixed population of critically il l patients was stopped early because of inadequate blood glucose control and risk of hypogl ycaemia. Both trials were underpowered for this effect. Two large, randomized trails on the infusion of glucose together with insulin and potassium in patients with diabe- tes and MI (DIGAMI-2) and patients with AMI (CREATE- ECLA) failed to show clinical bene \201 ts of t his treatment. In neither study was normoglycaemia achieved. Conclusions: (1) strict glucos e control is necessary to dem- onstrate bene \201 ts and (2) adequate power calculations a re crucial to produce meaningful studies. An ongoing study is the multi-center trial \200 \230Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulat ion \200\231 (NICE-SUGAR). decreased mortality decreased length of ICU stay prevention of acute kidney failure, anemia and hyperbi- lirubinaemia decreased need for prolonged mechanical ventilation and dialysis reduced incidence of critical illness polyneuropathy and/ or myopathy reduced incidence of hyperin \202 ammation and develop- ment of bloodstream infections improved long-term reha bilitation in patients with isolated brain injury improved long-term outcome of high risk c ardiac surgery patients reduced costs Hypoglycemia Tight glucose control with insulin carries the risk of hypoglycaemia. Severe o r prolonged hypoglycaemia can cause convulsions, coma and irreversible brain damage, as wel l as cardiac arrhythmias. In the surgical population the risk of hypoglycaemia (glucose \211 2.2mmol/l) increased from 0.8 to 5.1% with intensive insulin therapy and from 3.1 to 1 8.7% in the medical ICU population. Patients with sepsis appeared to be susceptible to the development of hypogly- caemia. These brief episodes of hypoglycaemia were not associated w ith obvious clinical problems: hypoglycaemia did not cause early deaths, and only minor imm ediate and transient morbidity was seen in a minority of patients, and no late neurological sequellae occurred among hospital survivors. The risk of hypoglycaemia did coincide with a higher risk of death in both conventional and intensive insulin groups. In a recent study, no causal link was found between hypoglycaemia in the ICU and death. These observations su ggest that hypoglycaemia in ICU patients who receive intensive insulin therapy may merely i dentify patients at high risk of dying rather then representing a risk on its own. Tight glucose management was evaluated in a heterogene- ous ICU population. Mean blood gluc ose was 7.3mmol/l in the protocol period, compared with 8.4mmol/l in the base- line period. There was a signi \201 cant decrease in hospital mortality, length of ICU stay, developme nt of new renal failure and red blood cell transfusions, as well as a reduc- tion in medica l costs. In a predominantly surgical patient population, glucose levels maintained between 4.4 and 6.7mmol/l (mean 6.9mmol/l) resulted in a decreased incidence of nosoco- mial infect ions. Mechanisms of actions of tight glycaemic control \200 \200 \200 \200 \200 Prevents immune dysfunction Prevents sustained systemic hyperin \202 ammation Improves dys lipidaemia Ameliorates muscle insulin sensitivity Protects the endothelium and mitochondria l ultrastruc- ture and function. Conclusion Maintaining normoglycaemia with intensive insulin therapy improves survival and reduces morbidity in surgical and medical ICU patients. Current evidence is in favor of con - trolling blood glucose levels below 6.1mmol/l in the ICU, despite a higher incidence of h ypoglycaemia. 427 CHAPTER 24.7 Glycaemic control in the critically ill Further reading CREATE-ECLA Trial Group Investigators. Effect of glucose \200\223insu- lin \200\223potassium infusion on mortality in patients with acute ST-seg- ment elevation myoca rdial infarction: the CREATE-ECLA randomized controlled trial. JAMA 2005; 293: 437 \200\223 46. NICE-SUGAR study: normoglycemia in intensive care evaluation and survival using glucose alg orithm regulation. Available from http://www.clinicaltrials.gov/ct/show/ NCT00220987. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345: 1359 \200\22367. Van den Berghe G, Wilmer A, Hermans G, e t al. Intensive insulin Glucontrol study: comparing the effects of two glucose control regimens by insulin in inten sive care unit patients. Available from http://www.clinicaltrials.gov/ct/show/NCT00107601. Hermans G, Wilmer A, Meersseman W, et al. Impact of intensive insulin therapy on neuromuscu lar complications and ventilator dependency in the medical intensive care unit. Am J Respir Crit Care Med 2007; 175: 480 \200\2239. therapy in the medical ICU. N Engl J Med 2006; 354: 449 \200\22361. Van den Berghe G, Wilmer A, Milants I, et al. Intensive insulin ther- apy in mixed medical/ surgical ICU: bene \201 t versus harm. Diabetes 2006; 55: 3151 \200\2239. 428 C KIRWAN & B PHILIPS Diabetic ketoacidosis Diabetic ketoacidosis (DKA) is a medical emergency that is characterized by hyperglycaemia, ketosis and acidosis This disorder primarily occurs in people with type 1 diabe- tes but a lso occurs in patients with type 2 diabetes. Urine \200 \200 CXR ECG Dipstick for ketones Microscopy and culture \200 Pathogenesis Ketoacidosis is a state of uncontrolled catabolism associ- ated with insulin d e \201 ciency. The absence of insulin causes an increase in hepatic glucose production, le ading to hyper- glycaemia. It also accelerates hepatic fatty acid breakdown producing exces s ketone bodies, which leads to ketoacido- sis. Concurrent osmotic diuresis and vomiting en hance \202 uid and electrolyte depletion. Subsequent renal hypoper- fusion results in imp aired excretion of ketones and hydro- gen ions, and the cycle self-perpetuates. Immediate management Dehydration is more life threatening than the hyperglycae- mia, so its correction takes precedence. Fluid The average \202 uid loss is 3 \200\2236l in DKA. The optimal rate at which \202 uid should be replaced is dependent upon the clinical state of the patient. \200 \200 0.9% Saline should be used initially. Fluids should be infused quickly when patients are in shock. An average regime may be: \200 \200 \200 \200 \200 \200 Causes \200 \200 Previously undiagnosed diabetes Stress of a concurrent illness \200 Interruption of insul in therapy \200 1l in 30min 1l in 1h 1l in 2h 1l in 4h 1l in 6h KCl should be added to each bag of \202 u id whilst mon- itoring the serum potassium level (see the electrolyte section) Most commonly UTI or pneumonia 25% of hospital admissions due to DKA are because the patient omitted their insulin Drugs \200 \200 Alcohol or substance abuse Corticosteroids Thiazide diuretics Patients who do not have an extreme volume de \201 cit may be effectively re-hydrated at a rate of 500ml/h for the \201 rst 4h followed by 250ml/h for the next 4h. More rapid resu scitation may not be necessary and can delay correction of the acidosis. Switch to dextrose saline when the blood glucose falls below 12mmol/l. Clinical presentation The symptoms and signs of DKA are related to hyperos- molality, volum e depletion and metabolic acidosis. History \200 Typically a 2 \200\2233 day history of gradual deterioration, per- haps precipitated by inf ection NB: the \202 uid regimes set out above are a guideline for patients with DKA. Excessive \202 uid can precipitate cerebral oedema, and inadequate \202 uid can lead to renal fail ure. Fluid management needs to be tailored to each individual patient and monitored careful ly throughout treatment Symptoms \200 \200 \200 \200 Polyuria and polydipsia Weight loss Vomitting Abdominal pain \200 Those of a concurrent i nfection/precipitating cause. Electrolytes Potassium Renal and GI losses contribute to a marked potassium depletion. Desp ite this, the plasma potassium concentration is usually normal or, elevated at presentation (1/3 cases). This is due to initial hyperosmolality and insulin de \201 ciency, which res ults in potassium movement out of the cells. \200 Can mimic peritonitis Signs \200 Volume depletion and shock \200 Hypotension, tachycardia, cool peripheries, low JVP, dry mucous membranes, increased skin t urgor There is a danger of hypokalaemia as glucose enters cells with insulin treatment Aim for a plasma K+ of 4 \200\2235mmol/l If K+ 3 \200\2234 mmol/l, aim to replace 40mmol KCl/h If K+ 4 \200\2235.5 mmol/l, aim to replace 20mmol KCl/h Measure plasma K+ every 2h Withhold K+ if oliguric (rare) or if initial K+ is >5.5mmol/l (the K+ will fall quickly as glucose re-ent ers cells) Acidosis \200 \200 \200 \200 \200 Kussmaul respiration, \200\230fruity odor \200\231 (specific to ketoacidosis) Neurological \200 Lethargy, visual disturbance, altered level of con- sciousness, seizures, coma Investigations \200 Sodium Reversing hyperglycaemia with insulin will lower the plasma osmolality, cause water to move from the extra- cellular \202 uid into cells, and raise the plasma sodium con- ce ntration. Thus, a patient with a normal initial plasma sodium concentration may become hype rnatraemic during therapy with insulin and 0.9% saline. Blood \200 \200 \200 \200 FBC U&E, glucose, LFT, CRP, amylase, osmolality Culture ABG (including lactate) 429 CHAPTER 24.8 Diabetic ketoacidosis 0.45% Saline is not, however, routinely used in the man- agement of DKA Add broad-spectrum antibiotics if infection is suspected Insert a bladder catheter if no ur ine has passed after 2h Place a central venous line if the patient is in shock or elderly t o assist the \202 uid management. \200 Phosphate The plasma phosphate concentration may initially be nor- mal or elevated, but pho sphate depletion is rapidly unmasked following insulin therapy, frequently leading to hypop hosphataemia. \200 Ongoing management \200 For the \201 rst 8h (at least): \200 \200 Adjust K+ replace ment according to results Alter insulin infusion and \202 uid type when targets are reach ed (see immediate management section) Seek the underlying cause Most patients remain asymptomatic and phosphate administration is not indicated. Monitor glucose hourly Monitior electrolytes 2 hourly Insulin Insulin lowers the plasma glucose concentration (primarily by reducing hepatic gluc ose production rather than enhancing peripheral utilization), decreases ketone pro- duction (by reducing both lipolysis and glucagon secretion) and may augment ketone utilization. \200 Complications and pitfalls in DKA \200 Patients may present with combined DKA and HONK (hyperosmolar non-ketotic ) Initial potassi um concentrations may be high but decrease rapidly after the initiation of treatment DKA ma y complicate type 2 diabetes mellitus as well as type 1 diabetes. Ketoacidosis is seen in a number of inborn errors of metabolism (often presenting in infancy) and in alcoholic and f asting ketoacidosis. It is unusual for the blood glu- cose to be raised in these conditions . IV bolus \200 6 \200\22310U stat Continuous IV infusion \200 50U of soluble insulin made up to 50ml with 0.9% saline to run through an infusion pump. St art infusion at 6U (6ml) per hour (10U (10ml) per hour if infection is present). Aim to low er the plasma glucose by 3.5 \200\2237mmol/l/h. When the blood glucose is <12 mmol/l, swit ch to either an insulin sliding scale protocol or the patients standard insulin regime. A m inimum infusion of 2U per hour should be continued until the ketoacidosis is corrected. Thi s may require co- administration of 5% dextrose. \200 Prognosis The mortality rate in patients with DKA is <5% in experi- enced centers. NICE guidelines Both IM and SC insulin therapy are as effective as IV therapy, if the patient is not in sho ck. However, their use is not recommended by most Diabetologists. There is con- cern that t he combination of volume depletion and secondary sympathetic activation decreases subcutane ous blood \202 ow, resulting in reduced insulin absorption. As normal blood flow returns, absorption improves and initial persistent hyperglycaemia can turn into delayed hypoglycae mia. http://guidance.nice.org.uk/topic/endocrine Further reading Adrogue HJ, Barrero J, Eknoyan G. Salutary effects of modest \202 uid rep lacement in the treatment of adults with diabetic ketoacido- sis. Use in patients without e xtreme volume de \201 cit. JAMA 1989; 262: 2108 \200\22313. Fisher JN, Kitabchi AE. A randomized study of phosphate therapy in the treatment of diabeti c ketoacidosis. J Clin Endocrinol Metab 1983; 57: 177 \200\22380. Acid \200\223base balance Trials do not demonstrate any clinical bene \201 t from the rout ine administration of sodium bicarbonate. \200 \200 