Diabetic coma

Diabetic Coma T. D. R. HOCKADAY K. G. M. M. ALBERTI

A death in diabetic coma destroys over 21 years of life, on average (Bradley, 1971). The essence of management is therefore avoidance of the 5 to 15 per cent mortality still reported from large centres. Long-lasting morbidity from tissue damage in the acute phase must also be prevented. While Bradley is correct in considering many coma deaths 'apparently unavoidable', this can only be accepted as a present, transitory state and not used as an alibi against endeavour to reduce mortality and morbidity further. Traditional regimens yielding acceptable results may evolve into schedules with more emphasis on tissue function than on plasma chemistry. However, earlier diagnosis and treatment may be the surest route to a better outcome.

PROGNOSIS

There is general agreement upon the important prognostic factors, although no one has matched the sophistication of Zieve and Hill's (1953a, b) analysis of mortality from 1930 to 1948. Their conclusions are not necessarily entirely applicable now with wider availability of antibiotics and more widespread understanding of intravenous (i.v.) fluid and electrolyte therapy. Considering factors singly, without reference to their interdependence, they found old age, low mean blood pressure, presence of severe 'associated conditiong and high blood urea to be bad prognostic signs, with degree and duration of coma less important, although with far greater influence, than blood sugar or plasma bicarbonate concentrations. However, analysis which allowed for interdependence of the variables removed age, for instance, as an important prognostic element, and gave weighting factors against presence of 'associated conditions' (e.g. infections, cardiac disease), degree of unconsciousness, duration of coma, and low blood pressure in the ratio of 140:67:10:3. Asfeldt (1965) noted that general clinical measures are prognostically more important than laboratory values for blood concentrations of ions or metabolites, completely in line with Zieve and Hill. Bradley gave 'complicating conditions', duration and degree of unconsciousness, and age as the key Clinics in Endocrinology and Metabolism--Vol. 1, No. 3, November 1972.

751

752

T . D . R . HOCKADAYAND K. G. M. M. ALBERTI

factors in the Joslin Clinic series, and Sheldon and Pyke (1968) identified age and degree of unconsciousness In our experience 'associated conditions', blood pressure, age and degree of unconsciousness have been the most vital prognostic factors. This raises three major questions: 1. Should one concentrate more precisely upon management of clinical features such as hypotension or disturbed consciousness, with some reduction in emphasis upon biochemical values ? To answer this, much more must be learnt about the control of the circulation and brain function in uncontrolled diabetes. 2. How can we translate the clues from blood analysis into understanding of cellular function and into measures to improve this function ? 3. What are the mechanisms that make age such a bad prognostic factor? This review will deal with the clinical and biochemical features of diabetic coma but wherever possible we shall consider pathophysiology and the ways in which disturbed metabolism saps tissue function.

DEFINITION: VARIETIES

Impairment of consciousness may be surprisingly slight in gross hyperglycaemia or severe acidosis, while among the few patients truly comatose (less than 15 per cent) some have remarkably mild alterations in blood chemistry. Hence diabetic 'coma and pre-coma' have become portmanteau terms for a combined metabolic and clinical state, and most definitions used to marshall clinical series contain highly subjective elements, e.g. diabetic with 'obvious and visible air hunger' (FitzGerald, O'Sullivan and Malins, 1961), or 'drowsy or unconscious with diabetic ketosis' (Sheldon and Pyke, 1968). Attempts to be more exclusive by measurement continue to include subjective elements, e.g. 'severe diabetic ketoaeidosis with a serum bicarbonate of less than 9 retool/1 (Root, 1959) and 'severe, uncontrolled diabetes requiring emergency treatment with i.v. water, electrolytes and insulin, with blood 'ketone bodies' (acetoacetate and 3-hydroxybutyrate) greater than 3 mmol/1 (Hockaday and Alberti, 1972). This last is given not as an advance in semantics, but because it defines our 'ketoacidotic' patients, some features of whom will be quoted later. In regard to definition, while 55 patients within this category were admitted in Oxford during 20 months, five were admitted who overlapped this group clinically but did not .qualify on blood ketone body analysis. Equally they could not be grouped with the seven patients with 'hyperosmolar non-ketotic diabetic coma' nor the three with 'lactic acidosis in a normoglycaemic diabetic', nor the four with combined lactic and keto-acidosis. Any definition of 'diabetic coma' should include ideally the varieties now identified, which emphasise the lack of correlation between disturbance of neuronal behaviour and change in any single metabolic measurement (e.g. blood glucose, lactate, ketone bodies, pH, serum osmolality, or plasma free fatty acids (FFA)). We need to know whether primarily physical factors (e.g. cell size or water content) or chemical ones (e.g. intermediary metabolism of

DIABETIC COMA

753

neuro-transmitters such as acetylcholine) limit brain-cell activity, and indeed which region of the brain fails in coma. Five varieties may be listed: KETOACIDOSlSwith hyperglycaemia and 'ketone bodies' above 3 mmol/l and reduced pH and/or blood buffering capacity. NON-KETOTIC

(i) Hyperosmolar non-ketotic with hyperglycaemia, 'ketone bodies' below 3 retool/l, but plasma osmolality increased above 330 mOmol/1. Most ketoacidotic patients have increased plasma osmolality, so that the blood ketone body content is the crucial distinction. (ii) Hyperglycaemic non-ketotic, a rarer, less well recognised variant, in which there is hyperglycaemia without ketosis but no increase in osmolality, because hyponatraemia offsets hyperglycaemia, with uraemia not gross enough to affect osmolality. DIABETICLACTICACIDOSIS"the diagnostic criterion is ~ blood lactate concentration of at least 7 retool/1 (Tranquada, Grant and Peterson, 1966). Lactic acidosis occurs frequently in non-diabetics, and may occur in diabetics with any blood glucose concentration. When lactate exceeds 7 retool/1 in the presence of ketoacidosis (in 4 of our 55) we classify the patient as ketoacidotic. DIABETIC URAEMIC COMA with grossly elevated blood urea (perhaps above 200 rag/100 ml) and acidosis with or without marked hyperglycaemia~ providing there is only moderate ketoacidosis and no lactic acidosis or hyperosmolality. No limit has been given above to hyperglycaemia. While ketoacidosis is uncommon with blood glucose below 300 rag/100 ml (18 mmol/1) it can occur at lower levels. Hypoglycaemia is the commonest cause of coma in insulintreated diabetics while diabetics may suffer any of the causes of coma that afflict non-diabetics.

MAJOR REVIEWS

The features and management of diabetic coma have been considered in a number of recent reviews (Bradley, 1971 ; D6rot, 1971 ; Hockaday and Alberti, 1972; McCurdy, 1970; Malins, 1971 ; Mohnike, Wappler and Bibergeil, 1971 ; Sheldon and Pyke, 1968; Winegrad and Clements, 1971). We shall not be comprehensive but shall discuss items of recent interest. However, we would re-emphasise the considerable differences among authorities as to detailed management of diabetic coma (Hockaday and Alberti, 1972). To underline this, Table 1 summarises advice from a number of text-books. One suspects that the wide differences cover features where considerable latitude does not crucially affect the outcome, while the summaries may well exclude features meriting greater attention. Why is it general experience t h a t arrangements within a hospital for special care of diabetic emergency admissions are followed by reduced mortality ? (Harwood, 1951 ; Hudson, Bick and Martin, 1960; our own series).

Table 1. Text book recommendations Reference

Insulin Dose

Saline & Water

Duncan (1971)

100u i.m. or in i.v. drip bottle with another 100u if glucose above 700 mg/ 100 ml. Further doses by blood results (No schedule).

Initially 'physio1-1.5 1. 0.85% saline in 30 min. logical', then ½ 0.5 I. alternating I of this. 1:2 with 5 % [ dextrose, 1-2 1. per hr for 2-3 h, then less.

Usually confusing: may be given as isotonic NaHCO3 or Na lactate.

100u s.c. (or

1 l./h 0"85 % saline,

'Physiological'.

Lactate solutions mentioned--not actively supported.

Hardwick (1970)

i.m., or i.v.) 2nd dose depends on initial glucose given at 2 h.

Na: Water Ratio

Alkali

London (! 970)

50-100u i.m. + 50-100u i.v. initial. 2nd dose at 2 h.

1 1.0"85% saline in 1st h, with added alkali 4 1. in 1st 12 h.

1.2 times 'physiological'.

30 mEq/l. NaHCO3 or alkali according to (25-plasma bicarb, mEq/1.) x 10 (mEq).

Williams (1968)

100u s.c. and 100u i.v. initial 50-100u (or 200) hrly. Reduce significantly when glucose 300 mg/100 ml.

After initial bicarb., 100 mEq Na, 60 mEq C1, 40 mEq HCO3 or lactate/I, for 1-3 h. Then 0.42 or 0.85 % saline.

0"6 times physiological, after initial isotonic alkali.

50-150 mEq NaHCO3 early; follow by Na lactate. Total alkali less than (25-plasma bicarb, mEq/l.) x 45 mEq~

Petrides et al (1971)

50-100 u i.v. initial, with 100u i.v, in drip over 1 h. 100u drip from 2-4 h.

1 1. in 1 h of 33 % 'N' saline, 33 % 'N' bicarb., 33 % water. 4-6 1. per 24 h. by age and severity.

0.67 physiological

Bicarb. from start, 50 mEq in 1st h, 50 mEq in next 2 h.

Kolb (1971)

100-200u, half i.m. half i.v.; repeat at 1-2 h, giving 50-75u every 1-2 h. till ketonuria lessens.

i.v. 0.45 %

0-5 physiological

If [HCO3] below 5 mEq/l., give 1.3 % NaHCO3 or M/6 lactate i.v.

(50% 'N') saline.

Steinke and Thorn (1970)

100u i.v. and 100u i.m. Then 100u at 2-4 h, if necessary.

0.85 % saline, 4-8 1. fluid in 24 h.

Physiological.

If [HCO-3] below 10 mEq/l. Amount not specified.

Bondy (1971)

50-100u i.v. initial, then 25100u per h i.v. or i.rn.

0"42 % saline with 2"5 % fructose. Rate not specified.

0.5 physiological

If [HCO'3] below 10 mEq/l., give [(25-plasma [HCO'3]) x 0.15 × Body wt.] mEq. Total dose at rate of 75 mEq/1. of fructosesaline.

for the treatment o f diabetic coma Potassium

Lv. Glucose

B.P. Support

Urethral Catheterisation

Gastric Aspiration

Non-Ketoacidotic

If vomiting has occurred.

Insulin 80 u/h. till glucose < 500 mg/ 100 ml 1-2 1. i.v. fluid hrly for 6 h, initial 11, 'N' 0-85 % saline, give 0-42% saline with 2.5 % glucose till glucose is 500 rag/100 ml; change to isotonic fluids.

Give i.v. if [K ÷ ] below 5 mEq/l. and urine output 'satisfactory', as 7-13 mEq/l, i.v. fluid; double if [K ÷ ] below 3 mEq/k

After ½h, as Nil special 5 % glucose in (i.e., insulin water, 2 and sodium). bottles to every 1 of 0.85% saline.

Do not.

Serious drop in [K + ] best corrected by 1 I. 5 % glucose plus 30 mEq potassium.

Deprecated Raise foot of early (See bed. previous column). Give as glucose approaches normality.

Do early if Do early if 0.42% saline, 2-3 1. unconscious unconscious. as quickly as possible. Insulin 20-40u initial. Add 52 mEq potassium to each 1. of 0'5 normal saline.

25 mEq/h i.v. Not after 4 h if urine discussed. output 'adequate'.

Central venous catheter is wise.

Not discussed.

Do early.

Less insulin than for ketoacidotic, 0.42 % saline.

Not discussed.

If gastric dilatation or persistent vomiting.

Much less insulin than in ketoacidosis, 0.42 % saline.

Half-'normal' saline with plasma expanders.

After 3-4 h (occasionally initially) usually 20 mEq/h, 100200 mEq/12h.

Blood glucose 1-2 units of plasma may below 300 rag/100 ml help.

20-40 mEq i.v. from start, if normokalaemic or hypokalaemic. Repeat hourly as necessary. Monitor E.C.G.

Blood glucose well reduced, give 5 % glucose. Later i.v. glucose or fructose.

500 ml plasma Do early. expander (e.g. Rheomacrodex) in 1st h. 500 ml if necessary in 2nd---4th h.

Do early if severe.

After 4-8 hrs, watch for potassium deficiency, and check E.C.G. Give buffered potassium phosphate, 40 mEq in 3-4 h.

Give i.v. once blood glucose begins rapid fall. Use 5 glucose in saline.

i.v. plasma for 'shock', with vasopressor if severe.

Do early.

Do early.

References given.

Start 2nd or 3rd h. Not more than 20 mEq/h. Rarely more than 80 mEq in 24 h.

When blood glucose approaches 200 rag/100 ml, use 50 % glucose in saline.

Blood, plasma Not or plasma specified. expanders.

In unconscious patients.

0.42 % saline; less insulin than ketoacidosis.

Usually not until When 'necessary'. 3-6 h. If initial [K + ] low, give 40-60 mEq/1. replacement fluid.

Blood or albumin with isoproterenol if necessary.

Routine antibiotics.

If unable to Not avoid, with specified. early removal.

Not specified.

756

T . D . R . HOCKADAYAND K. G. M. M. ALBERal DIFFERENTIAL

DIAGNOSIS

All patients with uncontrolled diabetes show physical signs of dehydration but only those with acidosis have air hunger, and only the ketotic have the characteristic odour on their breath; for those who cannot smell ketones, strong reactions in plasma or urine to 'Ketostix' or 'Acetest' are useful aids. Plasma tested with 'Ketostix' stored under usual ward conditions gives a ii IEI ¸' ~,i

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E ~i Iii fl

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o i

O O

8

• •

8

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o

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KETOSTIX

4- 4-

4-

READING

Figure 1. Ketostix readings with various concentrations of acetoacetate in blood, undiluted plasma (o), plasma diluted 1 in 2 with water, recalculated to original plasma volume (O),

DIABETIC COMA

757

wide range of values for a given Ketostix grade (Alberti andHockaday, 1972a) but Figure 1 shows how generally useful this test is in indicating the acetoacetate concentration. Absence of close correlation is not surprising because Ketostix react also with acetone, though at about one-seventh the sensitivity of acetoacetate. However, large amounts of acetone (2 to 12 mmol/1) are often present in ketoacidotic plasma (Sulway and Malins, 1970). A greater drawback to the significance of Ketostix readings is the absence of reaction with 3-hydroxybutyrate. This acid is present normally in twice the concentration of acetoacetate but the ratio may rise to 30 (Figure 2). Thus, in severe acidosis there may be a misleadingly small reaction with Ketostix. Blood pH should always be measured and if there is a discrepancy between pH and Ketostix, rapid enzymatic determination of both 3-hydroxybutyrate and lactate should be performed. •

::32

15

I0

Figure 2. Ratio of blood 3-hydroxybutyrate to acetoacetate in diabetic coma. (Shaded section indicates normal range). o o oo

.ore

3 - HYDROXYBUTYRATE ACETOACETATE

The only two conditions which are likely to be confused with classical diabetic ketoacidosis are piqure diabetes from hind-brain irritation and uraemic acidosis in a diabetic. Clinically a distinguishing feature may be the depressant effect upon the central nervous system of ketoacidosis, while undue irritability of the cerebro-spinal axis is common with fourth ven-

758

T . D . R . HOCKADAYAND K. G. M. M. ALBERTI

tricular lesions, non-ketotic hyperglycaemic coma or, indeed, during treatment of ketoacidosis. Such irritability may be seen principally in erratic oscillations of pupil size, respiratory rhythm or muscle tone, rather than in limb movements or epileptic discharge. Uraemic acidosis can really only be suspected when absence of lactic or ketoacidosis has been established (unless there is a previous history of severe renal disease) the optic fundi show hypertensive uraemic features (which may be difficult to distinguish from diabetic retinopathy), uraemic 'frost' can be seen, or a pericardial rub is present. Very high blood urea concentration and persistently high plasma phosphate must be demonstrated for uraemic acidosis to be fully accepted as the cause of 'air-hunger'.

PRECIPITATING FACTORS

Education about diabetes, from doctors to the public, must play a major part in changing the overall mortality from diabetic coma, even if it worsens the percentage results in hospital series (Bingle et al, 1971). One hopeful sign of the spread of knowledge about severe hyperglycaemic illness is that in the recent Oxford series reduction of insulin dosage was the cause of admission of only 7 per cent of cases, though whether as a consequence or not, infection was involved in the pathogenesis of 56 per cent of episodes, compared with a usual level of around 30 per cent. In addition to emphasis on the correct maintenance of fluid, calorie and insulin treatment during infection, especially when there is vomiting, it must be stressed that elderly patients maintained on oral hypoglycaemics can develop even ketoacidotic coma remarkably quickly if an infection is present. Such episodes will require a temporary spell of insulin treatment. Factors liable to precipitate coma have been discussed previously (Bradley, 1971; Hockaday, 1971) but iatrogenic factors need re-emphasis. These range from complex medical manoevres, such as peritoneal dialysis or extra-corporeal circulation, to frequently used agents. Glucocorticoids are well recognised in provoking the onset of clinical diabetes, but despite their recognised action in promoting lipolysis, they rarely cause ketoacidosis unless infection is also present. The role of thiazides is still controversial and must include factors inherent in the patient for its full assessment. However, the only three ketoacidotic patients in our series to have plasma potassium concentrations on admission of 3.0 mEq/1 or below were under treatment with thiazide diuretics and were 'new' diabetics. It seems that thiazides should be used with circumspection until experience with an individual has given some idea of his liability to develop diabetes during such treatment, and that they must always be accompanied by adequate potassium supplements. Phenformin is now well recognised as an associated factor in the development of lactic acidosis with or without hyperglycaemia (Woods, 1971). Renal or hepatic disease must be excluded before phenformin is prescribed. During phenformin treatment a close watch must be kept against the insidious development of lactic acidosis.

DIABETIC COMA

759

BIOCHEMICAL GENESIS KETO-ACIDOTICCOMA

The prime cause of diabetic coma is insulin deficiency. 'Normal' amounts of circulating insulin have been described by many authors but the concentrations are grossly inadequate for the degree of hyperglycaemia, and normal control of secretion is lost. In the initial stages of development of coma insulin administration is sufficient to correct the deficiency. However, very soon other systems become deranged as a result of the abnormal metabolic state and ultimately there are adverse effects on brain, muscle, kidney, heart, white blood cells, gut and buffer systems. Thus, ultimately treatment must encompass virtually every organ in the body. The breakdown of normal control can, however, be traced back to the imbalances in metabolic pathways induced by insulin lack. (For actions of insulin, see review by Randle, 1970). There are three main tissues involved: adipose tissue, liver and muscle. Adipose tissue The development of ketoacidosis stems from the effects of insulin lack on adipose tissue, with disruption of the normal or more specifically the glucose fatty acid cycle (Randle et al, 1963) (Figure 3). Normally, triglyceride is broken down to glycerol and FFA under the influence of 'hormone-sensitive' lipase. The lipase is activated by catecholamines, glucagon, cortisol, ACTH and growth hormone (mainly through cyclic AMP) and is inhibited by insulin. Glycerol cannot be phosphorylated by adipose tissue and is released into the circulation, acting as a gluconeogenic substrate in liver. The FFA either diffuse out of the fat cell or are re-esterified with a-glycerophosphate formed de novo from glucose. Insulin acts by stimulating glucose entry and glycotysis, as well as enhancing fatty acid synthesis. Thus, with insulin lack, re-esterifi'cation will be impeded, lipolysis accelerated, and incregsed amounts of FFA and glycerol released. The situation is exacerbated by the increased concentrations of cortisol, adrenaline and glucagon in ketoacidosis, acting further to accelerate lipolysis (Jacobs and Nabarro, 1969; D6rot, 1971; Unger et al, 1970). Liver Flux of FFA in plasma to the liver is increased, and acylation of the fatty acids occurs in the cytoplasm with subsequent 13-oxidation. Mitochondrial and cytoplasmic acetyl coenzyme A (CoA) accumulate in mitochondria and cytoplasm and acetoacetate is formed in excess. This is converted to 3hydroxybutyrate by the mitochondrial enzyme 3-hydroxybutyrate dehydrogenase, the final ratio of the two ketone bodies depending on the mitochondrial [free NAD]/[free NADH] ratio. Acetoacetate is formed in two ways: the condensation of two acetyl CoA molecules with direct deacylation and secondly further metabolism of acetoacetyl CoA through the 3-hydroxy3-methylglutaryl CoA (HMG-CoA) pathway (Figure 4). Williamson, in his review of ketogenesis (Williamson and Hems, 1970) believes the latter the more important. In alloxan diabetes there is increased activity of the key enzyme HMG-CoA synthase in both cytoplasmic and particulate fractions

GLYCOGEN

/

I

TISSUE

from liver,diet GLUCOSE

TRIGLYCERIDE

CHOLESTEROL

PYRUVATE--

/

......... \ TRIGLYCERIDE \

FFA'-

from adipose tissue

. GLYCOGEN

\

I

KETONE 7 "BODIES /

from liver

'---"1

PHOSPHATE

G,~CE.O,

GLUCOSE

iI

/

/

~ I

~

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• \

.,,TRIGLYCERIDES~ \

~.GLUTAMINE

, ,fLACTATE / / / / ALANINE "~

CHOLESTEROL~/

CO~,,~OL~ - ~ t ~ C02'1 PYRUVATE~

'GLUCAGON)' E~JNEP"R'NE'/'-~'I" : #(;LdCbSE-

S

KETOACIDOSIS

Figure 3. Metabolic pathways in liver and adipose tissue in the normal and ketoacidotic state.

/GLUCOSE GLYCIEROL /

,

/~/LACTATE / / ALANINE / ( GLUTAMINE

//

I N S U L I N /

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C02.

' GLUCOSE [ INSULIN'~It

/

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ADIPOSE

LIVER

NORMAL

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P

2~

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DIABETICCOMA

761

(Bates, Krebs and Williamson, 1968). There is also increased triglyceride synthesis, limited by the availability of a-glycerophosphate, and cholesterol synthesis from HMG-CoA is also enhanced. The rate of ketogenesis is determined largely by the plasma concentration of FFA (Start and Newsholme, 1968a). There is no evidence for significant ketogenesis occurring outside the liver. Many of the problems of diabetic ketoacidosis arise not simply because of increased ketogenesis (ketone bodies are essential fuels) but because production exceeds utilisation. Utilisation is determined by blood ketone body concentrations and is not definitely affected by insulin or glucose (Stadie, 1958). In the normal animal, administration of acetoacetate results in a prompt fall of plasma FFA due to decreased lipolysis which occurs even in the absence of insulin (Balasse, Couturier and Franckson, 1967; Hawkins et al, 1971). In diabetic ketoacidosis this normal feedback is lacking, with consequent excess ketone body production.

FATTY ACIDS

ACYLCoA

~ TRIGLYCERIDES

ACETYLCoA

I

r~ CITRATE

+ a

I

/

3-HYo o2 -¢- do YL-

ACETOACETATE .w---3-HYDROXY~--H BUTYRATE

-cos "a ACETONE

CHOLESTEROL Figure 4. The formation of ketone bodies in the liver. Normally, citrate is formed by condensation of oxaloacetate and acetyl CoA, a reaction catalysed by citrate synthase. In alloxan diabetes, hepatic citrate concentration is diminished, although the concentration of acetyl CoA is raised nearly three-fold (Start and Newsholme, 1968b). Thus, either citrate synthase activity or the amount of oxaloacetate must be decreased. ATP inhibits citrate synthase and in diabetes there is a large yield of ATP from fatty acid oxidation. More important, oxaloacetate concentration is decreased, partly by an increase in the NADH/NAD ratio because of fatty acid oxidation, and partly by markedly enhanced gluconeogenesis (Krebs, 1970). There is also inhibition of citrate synthase by long chain acylCoA

762

T . D . R . HOCKADA¥AND K. G. M. M. ALBERTI

derivatives which accumulate in liver in alloxan diabetes (Tubbs and Garland, 1964). The lack of citrate formation also decreases fatty acid synthesis. There is accumulation of acetyl CoA and acetoacetate formation. The liver lacks 3-oxoacid-CoA transferase (Williamson et al, 1971) with the result that acetoacetate and 3-hydroxybutyrate leak out into the circulation and serve as fuels for those tissues such as heart, kidney and muscle which possess the appropriate enzymes. Along with this large increase in ketone body formation there is markedly increased gluconeogenesis with little glucose oxidation (Greenbaum, Gumaa and McLean, 1971). Most of the energy required by liver is provided by fatty acid oxidation (Krebs, 1970). Glycogen content of liver falls to less than 10 per cent of normal in alloxan diabetes (Start and Newsholme, 1968b) due to glucagon and adrenaline stimulated glycogenolysis with failure of glycogenesis because of insulin lack. Insulin lack also results in failure of suppression of adenyl cyclase and glucose-6-phosphatase with the result that the normal restraints to gluconeogenesis are removed (see Newsholme and Gevers, 1967; and Lardy, 1970 for reviews). In experimental diabetes, several key enzymes of gluconeogenesis increase (Wimhurst and Manchester, 1970). Glucose is thus produced in excess and cannot be re-utilised because of the inhibition of glucokinase. Substrates for gluconeogenesis, in particular alanine and glutamine, are supplied in increased amounts, and the gluconeogenic hormones cortisol, glucagon, and adrenaline all increase the imbalance between glucose production and glucose utilisation. Gluconeogenesis also occurs in the kidney, though to an unknown extent in the uncontrolled diabetic. Muscle

Muscle is the main source of gluconeogenic precursors. Insulin normally stimulates amino acid uptake and protein synthesis (Manchester, 1968). Cortisol stimulates proteolysis. In uncontrolled diabetes when insulin is lacking and cortisol present in excess, there is a marked increase in amino acid flux from muscle. Glucose uptake by muscle is reduced because of insulin deficiency and further inhibition by the raised extracellular concentrations of fatty acids and ketone bodies (Randle et al, 1966). Fatty acids and ketone bodies serve as major fuels. Time course of the development

Because of ethical considerations it has proved difficult to carry out sequential metabolic measurements to determine in what order the metabolic derangements of ketoacidosis occur. Adipose tissue is more sensitive to insulin than muscle or liver (Zierler and Rabinowitz, 1964) so that in relative insulin deficiency, hyperglycaemia without hyperketonaemia would be expected. In experimental diabetic ketoacidosis in the rat the earliest changes are hyperglycaemia and an increase in glycerol and FFA which rapidly reach a steady state (Blackshear and Alberti, unpublished observations). On the other hand, blood ketone bodies and triglycerides rise more slowly but continue to increase

DIABETIC COMA

763

until death of the animal. Whether the rise in FFA or the rise in blood glucose occurs first is not yet known, but at most there is a 3-hour time difference. In the dog, increase in FFA and ketone bodies preceded eosinopenia, a crude index of adrenal secretion (MacArthur, 1954). Thus, insulin deficiency leads to decreased glucose utilisation, increased gluconeogenesis, increased lipolysis, increased ketogenesis, increased formation of triglycerides and cholesterol, and increased proteolysis. This is reflected in the blood by hyperketonaemia and increased levels of FFA, triglycerides and some amino-acids. Hyperglycaemia causes intracellular dehydration and an osmotic diuresis with the loss of water, sodium, potassium, chloride, phosphate, magnesium, calcium and nitrogen. Hyperketonaemia initially lowers the alkali reserve and later, blood pH falls. The hydrogen ion increase causes first, hyperventilation with further fluid loss and, secondly, displacement of potassium from cells with further potassium loss in the urine. More fluid and electrolyte is lost by vomiting. Impaired consciousness may be secondary to dehydration or to a direct effect of acetoacetate, but this remains controversial and awaits understanding of the intermediary metabolism of the neurotransmitters. HYPEROSMOLARNON-KETOTICCOMAAND HYPERGLYCAEMICNON-KETOTICCOMA Recent reviews have discussed the controversial points in the genesis of these types of diabetic coma (McCurdy 1970; Gerich, Martin and Recant, 1971; Jackson, 1971). There seems to be no single explanation for the absence of ketosis. The hyperosmolarity is often a result of dehydration combined with excessive carbohydrate intake (4 to 5 bottles of Lucozade a day in one of our patients, equivalent to about 600 g of glucose), and with impaired renal function the rise in blood glucose may be more rapid than otherwise because of reduced urinary loss. However, this is perhaps most important through cloaking symptoms of thirst and polyuria. Ketogenesis could be impaired because of failure to increase adipose tissue lipolysis, failure of acetyl CoA formation in the liver, or diversion of acetyl CoA from ketone body formation. Gerich et al (1971) favoured the first possibility, reporting low plasma FFA and citing as a cause lower levels of growth hormone (GH) and cortisol than they found in ketoacidotic patients (see also, Jacobs and Nabarro, 1969). Arieff and Carroll (1971) also found low circulating FFA. Circulating insulin sufficient to block lipolysis'but inadequate to cope with hyperglycaemia has also been suggested (Johnson et al, 1969), but we and several others have failed to find any difference between insulin levels in ketotic and nonketotic patients, just as the growth hormone values for the nonketotic are within the range of the ketotics. Again, there is controversy about FFA levels. We have found the same FFA concentrations in ketotic and nonketotic patients, while Vinik, Seftel and Joffe (1970) have reported six out of seven hyperosmolar patients with very high FFA levels. From Vinik's data one could suggest a block in hepatic uptake or degradation of FFA. Alternatively, there may be a block at the 3-hydroxy-3-methyl-glutaryl CoA step, with diversion to cholesterol (Williamson, personal communication).

764

T . D . R . HOCKADAYAND K. G. M. M. ALBERTI

Hyperglycaemia itself is thought to be antiketogenic, while hyperosmolarity can prevent adipose tissue lipolysis, but the hyperglycaemia and hyperosmolarity are not different enough from ketotic cases for this to be a useful explanation. We can but await further developments. LACTICACIDOSIS This has been reviewed by Oliva (1970) and Woods (1971). Lactic acidosis has been reported in association with many disorders. There is a higher incidence among diabetics than non-diabetics, and there is an association with phenformin therapy. In the absence of specific drugs, hepatic malfunction, permanent or temporary as from anoxia, is a prerequisite for development of lactic acidosis, for normal liver has an extremely large capacity for metabolising lactate (Berry, 1967). There will often also be a contribution through peripheral anoxia with increased glycolysis. The combination of ketoacidosis with lactic acidosis is rare. Using our criteria of 3.0 retool/1 total 'blood ketones' and 7 retool/1 blood lactate, Oliva found three cases, while Marliss et al (1970) reported one more and we have seen four cases. Lactic acidosis is probably commoner than this suggests because when ketoacidosis is present another cause of acidosis is not generally sought.

METABOLIC INVESTIGATIONS IN HUMAN DIABETIC KETOACIDOSIS Much of the last section concerned animal work. The next question is whether observations in man fit the concepts so derived or whether there are unexplained findings which demand modification of the generalisations about biochemical genesis. Recently developed techniques permit the measurement of many intermediary metabolites and hormones in small volumes of blood. No overall study of metabolites of carbohydrate, fat and protein metabolism in human diabetic coma has yet been published. However, reports of individual metabolites, when taken together, give a reasonable impression of the metabolic disturbance and its response to treatment. Fat metabolism

F F A levels before the start of treatment lie between 0.8 and 4retool/1 (Gerich et al, 19"11; Stcphens et al, 1971 ; our own series). We have found that plasma levels fall by 40 per cent in the first hour after the start of insulin therapy, sometimes preceding any change in glucose. On the other hand, glycerol, which is also elevated 4- to 5-fold (our own series; Dauchy et al, 1970) fell in the first hour in only 75 per cent of our subjects, and even then several of these showed a secondary rise. This discrepancy between FFA and glycerol can be explained in two ways. The first is that insulin switches off lipolysis but also inhibits gluconeogenesis from glycerol so that the half-life of plasma glycerol is increased. The second, and more attractive, hypothesis is of a differential effect on adipose tissue. If insulin re-establishes triglyceride

DIABETIC COMA

765

resynthesis in the fat cell, FFA release will fall abruptly. However, lipolysis is a function not only of insulin action but also of glucagon, adrenaline and cortisol effects. The concentrations of these last hormones are very high and remain elevated in blood for several hours after onset of treatment of coma (D6rot, 1971 ; Jacobs and Nabarro, 1969) so lipolysis may continue unabated with the release of excessive amounts of glycerol into the circulation. The role of hormonal antagonists is supported by the studies of Spergel, Bleicher and Ertel (1968) on patients with pheochromocytoma. In response to oral glucose, although FFA fell promptly, glycerol did not change, in contrast to the normal situation where F F A and glycerol fall together (Shafrir and Gorin, 1963). This dissociation of fall of FFA and glycerol was also noted by D6rot (1971), who then used the antilipolytic agent nicotinic acid in his patients and found a more rapid fall in FFA but an even more notable fall in glycerol. Blood ketone body concentrations bear no simple relation to those of FFA (Watkins et al, 1970; Willms et al, 1969). This is not surprising if one considers the different routes available to fatty acids in the liver, different rates of utilisation and urinary loss. In diabetic ketoacidosis, we consider 3.0 retool/1 total ketone bodies as the lowest limit of inclusion (normal fasting level is up to 0.15 mmol/1) although others might prefer a higher figure. Mean concentrations of 11 to 16 retool/1 have been reported, with values ranging up to 16 to 30 mmol/1 (Strandgaard et al, 1971 ; Stephens, Sulway and Watkins, 1971 ; Marliss et al, 1970; Zimmet et al, 1970; Alberti and Hockaday, 1972a). This represents a marked acid load and correlates inversely with pH. In normal man after an overnight fast, the ratio of 3-hydroxybutyrate to acetoacetate in blood is 1.5 to 3 (Wieland, 1968; Alberti et al, 1972a). Stephens et al (1971) found ratios of 1.3 to 4.8 (mean 2-7) in ketoacidosis, not too dissimilar from values in their non-ketotic patients. These values are lower than the 3-7_+0.3 found by us (Alberti et al, 1972b) and the 3-6+__0.4 of Marliss et al (1970), perhaps because Stephens et al (1971) used a non-enzymatic method of acetoacetate analysis. The ketone body ratio reflects liver mitochondrial [NADH]/[NAD], and the higher the ratio the more reduced the redox state of hepatic mitochondria. Gluconeogenesis, with its requirement of 6 ATP molecules per molecule glucose formed from lactate, will contribute to these high ratios, for it will initially raise the cytoplasmic [NADH]/[NAD] ratio. In the long-term this is transmitted to the mitochondria (Krebs, 1970). The ratio will also be raised if oxygen delivery to the liver is impaired (Brosnan, Krebs and Williamson, 1970). On treatment, the ratio falls (our series; Stephens et al, 1971). Separate analysis of the two ketone bodies shows this to result from an abrupt fall of 3-hydroxybutyrate, while acetoacetate may rise initially, to fall relatively slowly later. 3-Hydroxybutyrate is converted to acetoacetate before utilisation and this conversion may well be accelerated during treatment. There is also improvement in the hepatic [NADH]/[NAD] ratio following the abrupt cut-off of F F A supply to the liver and reduction in the rate of gluconeogenesis. However, it may take up to 24 hours for complete restoration to normal. Acetone formed by non-enzymatic decarboxylation of acetoacetic acid is also present in excess with concentrations up to 12 retool/1 (Sulway and

766

T. D. R. HOCKADAYAND K. G. M. M. ALBERTI

Malins, 1970). It is metabolically inert but relatively volatile so that it is exhaled. It is fat soluble and may persist in the expired air for many hours after the other blood ketone bodies have returned to normal levels. This also happens in the urine so that ketonuria cannot be used as a guide to further therapy. Lipoproteins, triglycerides, phospholipids and cholesterol are also present in increased concentration in most cases of ketoacidosis (Walton, Alberti and Hockaday, 1971 ; Tuller et al, 1954; Bagdade, Porte and Bierman, 1967; Harris et al, 1953). Occasionally there is profound lipaemia with lactescent serum. The serum lipids may then occupy 27 to 48 per cent of plasma (Chase, 1927). We have met only one such case among more than 50 ketoacidotic comas. Bagdade et al (1967), have demonstrated the presence of a 'Type 1 hyperlipoproteinaemia' with chylomicra and inhibited post-heparin lipolytic activity which returns to normal within 24 hours of treatment, with simultaneous decrease in triglycerides and cholesterol. Our own patients show a steady fall in triglycerides and pre-13-1ipoproteins over the 24 hours following insulin.

Lactic and pyruvic acids Blood lactic acid is frequently raised before treatment. We have found a mean value of 2.5 +_0.4 retool/1 (Alberti and Hockaday, 1972b) for venous blood while Watkins et al (1969), Marliss et al (1970) and Zimmet et al (1970) give the expected slightlylower values from arterial blood. There is a continuous graduation into lactic acidosis, so that accepting Tranquada's cut-off point of 7 retool/1 we have 4 patients with simultaneous lactic acidosis and ketoacidosis. After treatment, there is a highly significant negative correlation between initial blood lactate and change in lactate so that high lactates tend to fall and low ones to rise. Figure 5 shows data from two patients in one of whom blood lactate rose initially and in the other blood lactate started high and then fell. Plasma glucose and blood ketone bodies are also shown. The higher glucose and ketone bodies were found in the patient with the higher initial lactate but it is of interest that change in lactate bore no relation to change in glucose or ketones. An increase in lactate after insulin has long been known (Tolstoi et al, 1924), and recently emphasised by both Watkins et al (1969) and by Strandgaard et al (1971), although their data are sometimes difficult to interpret because of simultaneous lactate infusion. Certainly, there seems no justification for using i.v. lactate rather than bicarbonate to correct acidosis, a point made strongly by Schwartz and Waters (1962). Blood pyruvate follows the same trends, although it is proportionately not so elevated. The [lactate]/[pyruvate] ratio [L]/[P] is therefore elevated. Normally the ratio is about 10, while before treatment figures of 16 ±2 and 19 +_1 have been reported in ketoacidosis (Marliss et al, 1970; Alberti and Hockaday, 1972b). This probably reflects the redox state of the intracellular cytoplasm, together with the effects on [NADH]/[NAD] of intracellular [H ÷] concentration. It has been argued that the ratio cannot be equated with tissue oxidation (see Oliva, 1970, for discussion). We have found poor agreement between [L]/[P] ratios and [3-hydroxybutyrate]/[acetoacetate]

DIABETIC COMA

767

ratios. In our own series, the ratio fell slowly, and was stiU abnormal 5 and 24 hours after insulin though lactate and pyruvate and blood pH were then often within normal limits. At these times the ratio probably does reflect tissue redox state.

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Other organic acids Amino acid analyses have shown a marked reduction of the glucogenic amino acids, glycine, threonine, serine and glutamine (Felig et al, 1970; Alberti and Hockaday, unpublished data) but the ketogenic amino acids leucine, isoleucine, and valine are increased. It.seems that there is increased mobilisation of amino acids from muscle with increase hepatic extraction of glycogenic aminoacids. Serum uric acid concentration is also elevated in diabetic ketoacidosis (Padova and Bendersky, 1962) due in part to increased muscle protein catabolism but primarily because of decreased excretion in the renal tubule of uric acid, the ketoacids sharing the same secretory pathway (Goldfinger, Klinenberg and Seegmiller, 1965).

768

T . D . R . HOCKADAYAND K. G. M. M. ALBERTI

Hormones There is persistent elevation of plasma cortisol (up to 132 lag/100 ml), (Wallach, Englert and Brown, 1957; Wieland et al, 1965; Jacobs and Nabarro, 1969), glucagon (mean of 1700 pg/ml) (D6rot, 1971 ; Unger et al, 1970), and catecholamines (D6rot, 1971), all of which act as insulin antagonists. Their effects on gluconeogenesis and lipolysis were described in earlier sections. A similar role for growth hormone (GH) has also been proposed (Unger, 1965). However Cryer and Daughaday (1970) could show no correlation between serum growth hormone concentration and insulin resistance, although they did find pre-treatment values to be grossly elevated in a few cases, and most of their patients showed a further rise 1 to 3 hours after insulin was given. We have made serial growth hormone estimations in 37 cases of ketoacidosis (Alberti and Hockaday 1972c). Pre-treatment values were normal in females and mildly elevated in males. One hour after insulin there was a rise in all but four subjects. There was a positive correlation between the rise in G H and fall in blood glucose, and a positive, though weaker, correlation with pH. Two groups of subjects could be separated according to their G H response: those with a large response (a rise of more than 30 ng/ml) and those with a small response. The 'large response' group tended to be milder cases with lower plasma glucose, a greater rate of fall in glucose on treatment, lower blood ketone bodies, blood lactic acid and blood urea, and a higher blood p H than the 'small response' group. All deaths involved the 'small response' group. In that insulin resistance was more commonly found in the 'small response' group, it can be concluded that growth hormone, unlike the other anti-insulin hormones, is not important in this respect. The rise had disappeared by 5 hours, which again suggests that high serum G H concentrations can be ignored as a deleterious factor in coma patients.

Oxygen delivery to the tissues Effective energy production cannot occur without adequate tissue oxygenation. This demands adequate pulmonary ventilation, normal diffusion across the pulmonary endothelium, association of oxygen with haemoglobin, dissociation of oxyhaemoglobin in the tissues, diffusion from capillaries, and normal distribution of blood through the tissues at a reasonable flow rate and pressure. Two major facets are considered here; arterial oxygen saturation and dissocation of oxyhaemoglobin. ARTERIAL P O 2. In one third of our diabetic coma cases P02 was 80 mmHg or less. This, together with reduced blood volume, poor cardiac output and hypotension may well diminish oxygen supply. In several cases, blood lactate, and [L]/[P] ratios were raised more than would be expected from p H changes alone if associated with normal Po2 and adequate blood pressure, suggesting some other defect in tissue oxygenation. This is possibly a defect in oxygen release from haemoglobin, which is supported by lack of cyanosis despite a Po2 as low as 55 mmHg. Another factor must be that even with normal blood pressure, the mean distance between a cell and the nearest capillary is probably considerably decreased.

DIABETIC COMA

769

RED CELL 2,3-DIPHOSPHO-GLYCERICACID. In 1967, Benesch and Benesch, and separately, Chanutin and Curnish, showed that the affinity of haemoglobin for oxygen could be decreased by several organic phosphates. 2,3-diphosphoglycerate (2,3-DPG) was the most active, and is in high concentration in the erythrocyte, the molar ratio of 2,3-DPG to haemoglobin being close to 1. A rise in 2,3-DPG concentration will reduce the affinity of haemoglobin for oxygen with consequent shift of the oxygen dissociation curve to the right, and conversely a fall in 2,3-DPG causes a shift to the left with a diminished P50. This would reduce the release of oxygen to the tissues (see Oski and Delivoria-Papadopoulos, 1970, for review). This is shown diagrammatically in Figure 6 where in the example on the left, haemoglobin cannot release its oxygen, more dissolved oxygen diffuses out of blood and venous Po 2 is lower than in the normal (on right), despite inadequate release to the tissues. Red cell 2,3-DPG is low in several situations. These include acidosis, severe shock and storage of blood. Rorth (1970) showed that when pH fell below 7.4 there was a very sharp reduction in red cell 2,3-DPG, so that at pH 7.15 values were half normal. This would be sufficient to reduce the Ps0 from 27 to 20 mmHg with appropriate impairment of the diffusion gradient, though low pH itself would be acting conversely. Interest in red cell 2,3-DPG in diabetic ketoacidosis stemmed from the observations, first, that clinical and experimental metabolic acidosis reduce 2,3-DPG levels (Astrup, 1970) and, secondly, that low levels occurred during diabetic coma (Bellingham et al, 1970). This latter has since been confirmed by Ditzel (1971). The decrease in 2,3-DPG concentration is almost certainly due to increased [H ÷] which inhibits red cell glycolysis at the pbospofructokinase step (Rapaport, 1968). In both our own studies (Alberti et al, 1972c) and those of Bellingham et al (1971) there was a strong correlation between pH and red cell 2,3-DPG. The mean 2,3-DPG concentration in 16 of our patients was 2-2 retool/1 RBC compared with a normal of 4-5 mmol/1 RBC. This, of itself, would cause a marked shift to the left of the oxyhaemoglobin dissociation curve. However, all the subjects were acidotic and this causes a shift to the right in the curve (the Bohr effect). Bellingham et al (1971) have derived an equation relating Ps0, 2,3-DPG and Ps0 (the partial pressure of oxygen at which haemoglobin is half saturated. This states that : log Ps0 in vivo = log [26-6 + 0.5 (MCHC--33) + 0.69 (DPG--14.5)]+ 0.0013 BE + 0-48 (7.4--pH) + 0.024(T--37), where M C H C is mean corpuscular haemoglobin concentration, DPG is given as gmol/g Hb, BE is base excess and T is patient temperature. Using this equation we have a mean Ps0 of 28.8 mm Hg in our patients compared with 26.6 in normals and 29.9 in Bellingham's four patients. Thus, in diabetic ketoacidosis oxygen dissociation is normal and the decrease in 2,3-DPG is a protective mechanism against the deleterious effects of a fall of pH, and not just another metabolic aberration. Any tissue anoxia can therefore not be attributed to change in 2,3-DPG concentration. These values are all from untreated patients. Treatment on the other hand creates an imbalance between 2,3-DPG and pH. It may take 96 hours for 2,3-DPG to return to normal while pH is generally normal by 24 hours. At

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this time therefore there is a shift of the curve to the left, confirmed by calculation. This is accentuated if alkali is given early in treatment (Bellingham et al, 1970), confirmed by our own observation that despite p H increase, [lactate]/[pyruvate] ratios remain high. This is another reason for avoiding the hasty use of intravenous bicarbonate. Precise measurement of oxygen dissociation from haemoglobin under such varying conditions is needed. The long time required for 2,3-DPG to return to normal may be due to the profound fall in plasma inorganic phosphate seen in the early phase of treatment of coma. Decrease in phosphate is one of the factors that can cause a fall in red cell 2,3-DPG (Rapaport and Guest, 1938). Guest and Rapaport (1948) and our own series have shown that it may take several days for the red cell 2,3-DPG and plasma phosphate to return to normal. Travis et al (1971a) observed increased 2,3-DPG levels after phosphate administration to a patient with low plasma inorganic phosphate. It seems reasonable to augment normal i.v. therapy with inorganic phosphate in the treatment of coma. Travis et al (1971b) have suggested another reason for the 2,3-DPG deficiency. When they incubated red cells in a high glucose (50 retool/l) medium there was a marked increase in the conversion of glucose to fructose and sorbitol, together with a rise in the N A D H / N A D ratio and a fall in 2,3D P G concentration. This stimulation of the polyol pathway by hyperglycaemia with reduction in glycolysis may be a cause in vivo of the reduced 2,3DPG. In our series there was no correlation between 2,3-DPG and plasma glucose concentration suggesting that pH, not glucose, is the major determinant of red cell 2,3-DPG in diabetic ketoacidosis. The several factors relevant to 2,3-DPG in diabetic coma are summarised in Figure 7. Glucose conversion to sorbitol, acidosis and low phosphate all reduce 2,3-DPG, while the raised pyruvate found in many coma patients will tend to combat this. Defective oxygen release may also account for some findings relating to depth of coma (Kety et al, 1948). Cerebral oxygen utilisation was 2.0 ml/100 g brain per minute in comatose patients and 2.4 ml/100 g or more in conscious patients. The decrease was correlated with neither cerebral blood flow, Po2, nor p H but was related to blood 'ketone body' levels.

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772

T . D . R . HOCKADAYAND K. G. M. M. ALBERTI SYNOPSIS OF MANAGEMENT OF KETOACIDOSIS

Knowledge of the underlying mechanisms or detailed metabolic changes of diabetic coma has to be translated into practical terms. Below is the outline of our present protocol for the treatment of diabetic ketoacidosis. Any such scheme must be flexible enough to cope with different presenting features a n d individual responses to treatment. INITIAL

1. Rapid clinical examination. 2. Draw blood for Ketostix, blood sugar, Hb, PCV, urea, electrolytes, cross-matching and blood culture, and arterial blood for pH, Pco2, Po2. 3. Aspirate stomach. 4. Start fluid replacement with isotonic NaC1, one litre in 30 minutes, then 500 ml per 30 minutes. Exclude cardiac failure. Give 1 g KC1 in first hour unless patient old or extremely ill. 5. Give insulin i.v. and i.m. according to plasma Ketostix reading (Table 2). 6. Record E.C.G. Attach patient to cardiac monitor. 7. Give 100 per cent oxygen unless Po2 known to be over 80 mm Hg. 8. Catheterise if no urine is passed in first 4 hours (or patient then incontinent), or earlier if necessary facilities for blood biochemistry are unavailable. 9. If evidence of infection, or urethral catheterisation is necessary, culture appropriately and begin antibiotic therapy. I0. Consider central venous pressure line if any question of cardiac impairment. Table 2. Initial Insulin Therapy According to Ketostix Ketostix reading Plasma undiluted

Plasma diluted 1 + 1

+++ + + + + + + + + + + + Less

+++ + + + + + Less Less Less

Insulin dose Plasma diluted 1 + 3 +++ Less Less Less Less Less

i.v.

i.m.

120 180 80 120 60 90 40 60 30 50 Stop and Think Await blood glucose

FURTHER MANAGEMENT

1. If pH below 7-0, give 125 mmol NaHCO3 with 1-5 g KC1 in 30 minutes. If pH 7.0 to 7.1, give 50 m m o l NaHCO3 with 1 g KC1 in 15 minutes, repeating dose 30 minutes later. Repeat pH measurement 1 to 2 hours after bicarbonate and give further treatment accordingly. 2. Repeat glucose, urea, electrolyte and Ketostix measurement one hour after first dose of insulin. 3. Continue i.v. isotonic saline 500 ml per 30" minutes for 1 more hour (if good cardiac function). Then give 500 ml, hourly. When blood glucose below 250 rag/100 ml change i.v. fluid to 5 per cent glucose (w/v) or 4 per

DIABETIC COMA

4.

5.

6.

7. 8. 9.

773

cent glucose (w/v) in N/5 saline (31 mEq/1), 500 ml every 2-4 hours depending on state of hydration. Further insulin doses. Give second dose at 1 to 2 hours depending on 1-hour glucose and Ketostix values. (a) ff glucose has risen, give double initial insulin dose. (b) If glucose and ketones unchanged, repeat initial insulin dose. (c) If less than 25 per cent fall in glucose, and ketone bodies have decreased, give half initial insulin. (d) If blood glucose has fallen more than 25 per cent, give insulin units as 1-hour blood glucose value divided by 10, 40 per cent i.v. and 60 per cent i.m., unless glucose less than 400 rag/100 ml when no more insulin should be given. Assess situation again 5 hours after first insulin and treat according to above schedule. In severe cases consider third dose on basis of 3-hour blood results. If initial plasma potassium les~ than 4.0 mEq/1 give 3 g KC1 per hour i.v. for 2 hours (second and third hours), then 1 to 2 g per hour. Similarly, if fall to less than 3.5 mEq/1 by one hour give at least 3 g per hour with 5 g per hour if K + less than 2.5 mEq/1. If initial K + 4-0 to 5.0 mE/1 give 1 to 2 g per hour for 3 hours, ff initial K + more than 5.0 give 1.0 g KC1 in first hour and resume only when K + below 4.5 mEq/1. Proceed with caution if subject is anuric or has systolic blood pressure below 90 mm Hg; rapid i.v. potassium is safe only with cardiac monitoring. ff systolic B.P. falls to 80 mm Hg or less, and signs of peripheral vasoconstriction (cold hands, oliguria), begin blood infusion, or plasma if blood not yet available. If no improvement after 2 units (1 litre) consider use of isoproterenol. Use half-hourly Dextrostix from 2½ hours to detect hypoglycaemia. Watch carefully for cardiac, respiratory and renal failure. If no significant improvement by 4 to 5 hours repeat blood testing, and look for other cause of continuing coma.

ASPECTS OF MANAGEMENT The preceding section gave our present practical approach to the management of ketoacidosis. In this section we discuss some features which remain controversial. KETOACIDOSIS

Insulin sensitivity and resistance In a much-quoted paper by Walker et al (1963), insulin resistance was equated with acidosis. In seven patients, measurements of pH were made on capillary blood, and insulin resistance was calculated from the formula: Initial blood-sugar Total dose of insulin X Absolute fall in blood Total time in hrs since sugar starting treatment The dose of insulin varied from 100 to 200 units with big variations in intravenous replacement fluids. They also showed that glucose oxidation and glucose uptake by rat epididymal fat pad and glucose uptake by isolated rat hemidiaphragm fell sharply with pH, but many observations were made at unduly low pH.

774

T . D . R . HOCKADAYAND K. G. M. M. ALBERTI

We have used a simpler formula for calculation of initial insulin sensitivity: Absolute fall in blood glucose in 1 hour Total initial insulin dose. We found a curvelinear relation between insulin sensitivity and arterial blood pH. However, not surprisingly, those patients with the lowest pH values received the highest doses of insulin, and if there is a concentration above which additional insulin has no immediate effect then such a relationship would be produced artificially. Such a 'saturation' effect for insulin has been suggested by S6nksen et al (1971). Analysing a relatively homogeneous group of our patients who received between 80 and 100 units of insulin, there was no relation between sensitivity and pH. Overall, we distinguish two separate groups: one with normal pH and high sensitivity (4 to 5 rag/100 ml/unit insulin/hr) and one with pH below 7.35 and low sensitivity (less than 2rag/100 ml/unit/hr). No difference could be detected between those with pH of 6.9 or less and those with pH 7.15 to 7-25 We suggest that insulin resistance is a function of the causative factors of ketoacidosis, such as cortisol, glucagon, epinephrine, ketone bodies and FFA, with perhaps some direct contribution from pH, rather than any simple function of [H +].

Intravenous fluids and electrolytes SALINE. In ketoacidotic coma we usually start i.v. fluid replacement with isotonic saline. The first litre is given in 30 minutes and the second litre in one hour. In the presence of heart failure or significant myocardial damage the rate may be slowed and is monitored with a central venous pressure line. In hyperosmolar coma or ketoacidotic coma with hypernatraemia, 0.45 per cent saline (77 mEq/1) is substituted for isotonic saline, and subsequent replacement guided by plasma sodium concentrations. Isotonic saline is therefore usually given until the blood glucose falls below 250 rag/100 ml when 4 per cent glucose (w/v) in 1/5th N saline (31 mEq/1) or 5 per cent glucose (w/v) in water is begun. There is a greater total body deficit of water than of sodium so that mild hypernatraemia and hyperchloraemia almost inevitably result in the early stages of treatment. This must tend to prolong acidosis, but to a physiologicallyinsignificant extent. More important, it may slow the flux of water into cells by maintaining extracellular osmolality despite falling blood glucose. Too rapid an increase in intracellular water may be harmful, especially in the brain. We have not seen any cases of cerebral oedema, which have been reported from centres using hypotonic solutions (Young and Bradley, 1967) while patients so treated have been found to have high C.S.F. pressures (Clements et al, 1971). POTASSIUM. Although balance studies have shown deficits of total body potassium of approximately 500 mEq (Butler et al, 1947; Nabarro, Spencer and Stowers, 1952a), advice about intravenous potassium infusion remains remarkably cautious. It is usually recommended that i.v. potassium be delayed until 4 hours after insulin and started then only if urine flow is well established (at least 40 ml/hr), in spite of long-standing recognition of considerable

DIABETIC COMA

775

hypokalaemia during treatment (Harrop and Benedict, 1924). Perhaps because of the long interval in earlier studies between insulin injection and the first observations of potassium concentration, hypokalaemia was thought a relatively late complication of treatment--and indeed, obvious clinical effects of hypokalaemia were usually delayed for 8 to 20 hrs after insulin (Holler, 1946; Nicholson and Branning, 1947). These include respiratory paralysis; weak, flaccid and areflexic muscles; abdominal distension with paralytic ileus; and cardiac enlargement and failure. However, one should watch for less obvious features, such as failure of return of muscle tendon reflexes as pH returns to normal, or development of a wide pulse pressure out of proportion to the extent of rehydration (Bradley and Rees, 1963). More important is cardiac dysrhythmia, often transient but sometimes rapidly fatal. The E.C.G. is a useful guide to the potassium state, for it reflects the balance between extra- and intra-cellular potassium. Serial recording is necessary but many changes are non-specific. Roberts and Magida (1953) showed experimentally how various factors could mimic effects of changes in potassium concentration, with acidosis resembling hyperkalaemia, and increase in plasma sodium resembling hypokalaemia. The height of the T wave can only be used as a crude index of plasma potassium when the ST segment is normal in duration but the Q-T interval is prolonged (Nadler, Bellet and Lanning, 1948). Thus, the record must never be thought equivalent to determination of plasma potassium though it provides a rapid index of cardiac excitability and a useful guard against hyperkalaemia during potassium infusion. The frequent reports between 1945 and 1955 of low plasma potassium and the effects of alkaline infusion linked hypokalaemia with i.v. bicarbonate, as well as with large doses of insulin and i.v. glucose. Only Martin, Smith and Wilson (1958) had enough data to justify their recommendation of i.v. potassium early in treatment, but they suggested only the relatively small dose of 13 mEq/1 i.v. fluid, with the proviso that urine flow was adequate. Only recently has early use of i.v. potassium been generally accepted. By 1971, three reviews of treatment of diabetic comas were all recommending more and earlier i.v. potassium (Hockaday, 1971; Malins, 1971; Winegrad and Clements, 1971), supported by experience such as Glynne's (1960). He described, out of 36 patients in ketoacidosis seen over 7 years, four with initial serum potassium less than 3.6 mEq/1 of whom two died within a few hours, while three died out of the five with initial values between 3.6 and 5-0 mEq/1. Another influence was the increasing recognition of occasional patients with potassium 'sinks', requiring i.v. infusion of 350 to 700 mEq potassium (Clementsen, 1962; Abrahamson and Arky, 1966; Pullen, Doig and Lambie, 1967) with rates as high as 80 mEq/hr or even, in an extreme situation, 27 mEq/5 rains (Sheldon and Pyke, 1968). Review of the Oxford data gives some quantitative guidelines (Hockaday, Alberti and Wilkinson, 1972). The mean plasma potassium of 47 ketoacidotic patients on admission was 4.4 mEq/1 which had fallen to 3.5 mEq/1 after 1 hr of treatment, which in only a minority of patients included i.v. potassium.

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The decrease after one, and indeed five hours was strongly dependent on the initial potassium concentration. Because of the data from the first 22 patients, i.v. potassium was infused more readily in the next 25. The rapid disposal of potassium within the cells was shown by a mean plasma level of only 4.0 mEq/1 5 hrs after the start of treatment when 87 mEq had been given. The decrease in plasma potassium after 5 hours was inversely correlated with the potassium infused (r=0-74, p < .001), and from this relationship one could deduce, for the 'average' patient that if no potassium had been given, the mean concentration would have dropped to 2.3 mEq/1 at 5 hrs. Alternatively, to prevent any fall in potassium during treatment almost 120 mEq/1 would be needed in the first 5 hrs. This may be contrasted with the calculations of Scribner and Burneil (1956) who reckoned that a drop of 1 mEq/1 from a serum potassium of 3 mEq/1 represented a loss of total body potassium of 200 to 400 mEq. Such a value is bound to be greater than a 5 hr replacement figure, and is probably dependent on the lower reference concentration. A low rate of cellular influx at low plasma values, with rapid increase in entry for small plasma increments led to statements such as 'potassium entry into cells occurs only if exogenous potassium is supplied' (Elkinton, Winkler and Danowski, 1948). During the first 24 hrs, too, there was a firm, inverse correlation between potassium retention (i.v. potassium minus urinary potassium) and initial potassium concentration, not explicable by the expected relationship between initial potassium and amount of potassium infused. There was also an 'obligatory' urinary loss of potassium of some 50-100 mEq regardless of the potassium infused, perhaps reflecting impaired renal reabsorbtion. Finally, the three patients with initial plasma potassium concentrations below 3 mEq/1 were 'new' diabetics, 48 yrs or older, treated by thiazide diuretics for at least 2 months, with added potassium prescribed in only one. Nonetheless, i.v. potassium should be used with care, and the following points remembered when deciding potassium therapy: 1. Despite notable hypokalaemia most patients show little or no clinical disturbance from it. Particular care is needed during i.v. bicarbonate infusion, which we regard as a direct indication for i.v. potassium except in the most hypotensive and ill patients known to be severely hyperkalaemic. For instance, in one patient 1 hr after the first dose of insulin the plasma potassium has fallen only from 7.1 to 6.2 mEq/1 but nonetheless 13 mEq potassium were given with 100 mEq sodium bicarbonate, as more insulin was also being given and because the blood pressure had improved (there was no knowledge of urine formation). Two hours later the plasma potassium had fallen to 3.9 mEq/l, 2. If a patient shows hypotension not readily responsive to i.v. saline, cells may fail to take up potassium even after i.v. insulin has been given, and may continue to leak potassium from the intracellular to the extracellular space. Such patients have a grave prognosis, and this will be worsened by i.v. potassium. Such patients are, however, now relatively rare, and there are far more reports of diabetic coma deaths in hypo- than in hyper-kalaemia.

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BICARBONATE. Severe acidosis may impair cardiovascular function by a negative inotropic effect, and respiration by a direct depressant effect on the respiratory centre, after the initial stimulation. It therefore seems wise to treat the more severe cases with alkali and to diminish the excessive work of breathing; the patient may be conscious enough to be distressed by the air hunger. However, there is little agreement on the metabolic or overall benefits that accrue from bicarbonate, the amount to be given or the rate of administration, although most authorities advocate that at least some alkali should be given. Hartman (1935), in a classic study in children, compared treatment without alkali against treatment with sodium bicarbonate or sodium lactate. There was no difference in mortality but sodium lactate gave the quickest elevation of plasma carbon dioxide content. Asfeldt (1965) in a consecutive series could also find no difference in mortality between patients who did not receive alkali and those given bicarbonate. There is no study therefore which shows a clear clinical advantage of the use of alkali, but most studies measure clinical advantage by mortality alone. There are several reasons for moderation in alkali replacement therapy. Zimmet et al (1970) calculated the alkali requirement by the formula 0.3 x body wt in kg x (25--plasma bicarbonate mEq/1)mEq and the mean deficit appeared to be 394 mEq. However, in practice, 185 mEq corrected the pH to normal values and such a discrepancy is common experience. Posner, Swanson and Plum (1965) infused alkali, and observed an initial decrease in C.S.F. pH, which could be harmful. Also rapid correction of pH will shift the oxygen dissociation curve further to the left which could result in poorer oxygen supply to the tissues. Rapid correction of pH can additionally cause a rapid movement of potassium into cells, aggravating the insulin induced flow of potassium from the extra- to the intracellular compartment, but this can be covered by adequate i.v. potassium. We have also shown that insulin sensitivity is not related to pH except in very crude form. Ideal treatment i.e. adequate amounts of insulin to prevent excessive ketone body (and seemingly lactate) formation must cut off the supply of H ÷ ions. However, we have been impressed by the symptomatic relief afforded by alkali in the severely acidotic patient. Our aim is to return arterial pH quickly to between 7.1 and 7-2. We use bicarbonate alone; lactate has no place in modern alkali therapy. Potassium is always given with the alkali (7 mEq K+/50 mEq NaHCO3). PrtOSPnATE. During the development of ketoacidosis there is a significant loss of inorganic phosphate. This has been estimated at between 0.5 and 1-3 mmol/kg body weight (Butler et al, 1947; Nabarro et al, 1952a; Martin et al, 1958). As with potassium, there is a marked egress of phosphate from cells so that plasma concentrations may be elevated before treatment is commenced; 4 to 6 rag/100 ml are typical pretreatment values (Root, 1959), and impressive falls occur after treatment. Several of our patients had values of less than 1 rag/100 ml 24 hours after the beginning of treatment, and several days are sometimes necessary for this to return to normal. Martin et al (1958) made similar observations.

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Thus, there seems good reason for adding phosphate to i.v. replacement regimes. This has been recommended in the past by Nabarro et al (1952b), Butler (1950), Harwood (1951), Martin et al (1958) and Daughaday (1958), but is seldom mentioned in recent publications. Although Winegrad and Clements (1971) recommend potassium as the phosphate, Bradley (1971) goes so far as to recommend not using it on the grounds of complexity, and Malins (1971) has not found its use clinically advantageous. This may be because little clinical advantage has come from the use of i.v. 'mixed grills' (mostly hypotonic). However there is a good correlation between the continued low concentrations of plasma phosphate and red cell 2, 3-diphosphoglycerate (2,3-DPG). Travis et al (1971a) have recently shown that red cell 2,3-DPG falls when plasma phosphate falls and can be restored to normal with i.v. phosphate administrations. It may be that the reintroduction of phosphate into intravenous replacement regimes will result in the more rapid restoration of 2,3-DPG to normal with consequent improved tissue oxygenation. Furthermore, earlier use of larger infusions of potassium may exacerbate the decrease in plasma phosphate, and expose a need for i.v. phosphate. FRUCTOSE.There is no place for the use of fructose in the treatment of diabetic ketoacidosis. Interest arose when fructose was found to be antiketogenic and to be metabolised in the absence of insulin. It was reasoned that it could provide useful calories and act as an energy source when there was impaired metabolism of glucose. Rosecan and Daughaday (1954) in a classical study showed that in ketoacidotic patients fructose caused a 50 per cent fall in blood ketones with a moderate rise in blood glucose when given without insulin. Insulin given with glucose or fructose caused a bigger fall in blood ketone concentration than insulin alone, while there was a better fall in blood glucose with fructose than with glucose. Nabarro, Beck and Stowers (1955) compared patients treated with and without fructose in diabetic ketoacidosis and were unable to show benefit from the use of fructose. There are several reasons why fructose may be harmful. Root, Stotz afad Carpenter (1946) and Miller et al (1952) showed that fructose caused a marked rise in blood pyruvate, and, presumably, lactate in diabetic patients while glucose had only a minimal effect. Bergstrom, Hultman and Roch-Norlund (1969) showed that infusion of lg/kg body wt per hour caused a 5 mmol/1 rise in blood lactate with significant worsening of the pre-existing acidosis and hyperglycaemia. There is thus a possibility that fructose will increase any tendency towards lactic acidosis. Miller et al (1952) also showed that fructose caused a marked fall in plasma phosphate while more recently Maenpaa, Raivio and Kekomaki (1968) have shown in experimental animals that fructose causes a 40 per cent fall in hepatic adenine nucleotides, with ATP particularly affected. Lastly, fructose increases plasma uric acid in man (Perheentupa and Raivio, 1967), although this has not been corroborated in normal subjects (Sahebjami and Scalettar, 1971). Uric acid is already high in ketoacidosis and there seems little point in raising concentrations even further. If adequate insulin is given, there is no reason why glucose, already present in large amounts, should not be a sufficient energy source. Some authorities

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such as Mohnike et al (1971) still recommend fructose, but we cannot agree with this. Sorbitol and lylitol are also antiketogenic and their use has been suggested (Hiither, 1965; Toussaint, Roggenkamp and Bfissler, 1966) but, as with fructose, there seems little clear evidence in their favour although they are not as lactatogenic.

Hypotension Hypotension, particularly if sustained after the first hour of intensive isotonic saline therapy and insulin action, is usually a grave feature. Treatment of hypotension is one of the least studied elements in coma management. Undescribed differences in approach may account for differences in mortality between various series. The sustained success of the Joslin clinic has been obtained with blood transfusion in 'relatively few patients' (Root, 1959). However, the occasional, apparently unpredictable occurrence of cardiovascular collapse some hours after start of treatment makes us now include grouping and cross-matching of blood among our initial measures. Low blood pressure may be an over-riding problem before blood is available for transfusion. Bradley (1971) recommends low molecular weight dextran while others use human plasma but this must always carry a risk of viral hepatitis. The cause of sustained hypotension is uncertain. Contributing factors include hypovolaemia from sodium and water deficiency, reduced contractile force of a metabolically abnormal heart (Oliva, 1970), and peripheral vasodilation, stimulated by acidosis, hypokalaemia, and lactacidaemia. Howarth, McMichael and Sharpey-Shaefer (1948) pointed clearly to decrease in the peripheral vascular resistance as the major factor in hypotension, except for the occasional instance of cardiac infarction coincident with, and often precipitating, ketoacidosis. Partamian and Bradley (1965) have made two important points about the combination: diagnostically, about one-fifth of infarcts in diabetics are clinically silent (as opposed to under I0 per cent in non-diabetics), while infarction and ketoacidosis carried a mortality of 90 per cent. , Sustained hypotension may be the pointer to a number of other complicating factors apart from myocardial infarction, and of these gram-negative septicaemia, staphylococcal infection, renal papillary necrosis, haemorrhagic pancreatitis, gastrointestinal haemorrhage, or acute adrenal insufficiency are the most likely. The threat they pose requires blind i.v. antibiotic treatment, provided blood cultures are set up first; watch upon plasma calcium and consideration of i.v. calcium therapy; and trial of i.v. hydrocortisone, despite its diabetogenic effect. The intra-gastric tube should warn of gastric haemorrhage, not to be confused with slight oozing from the gastric lining. The essence of treatment must be fluid that stays in the vascular compartment. An added advantage of treatment that raises the tonicity of the E.C.F. will be prevention of too-rapid entry of fluid into the intra-cellular compartment, lessening the risk of water intoxication. Central venous pressure monitoring is advisable.

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Bradley (1971) recommends packed red cells unless the haematocrit is below 24 per cent or active bleeding has been identified but this has no advantage over whole blood if peripheral vasodilatation is indeed the problem. However, the immediate choice is usually between plasma, dextran, or large volumes of saline. Plasma may introduce the hepatitis virus which carries an appreciable mortality. Dextran has been suggested as a cause of renal damage when given at a time of very low renal blood flow, although such damage is usually reversible. We use plasma at present, but this may not be good practice in all countries. The value of vasoconstrictor stimulation or blockade is as doubtful as in any 'shocked' patient, but potentially useful agents are metaraminol or nor-adrenaline, especially if given relatively early, and 13-stimulator isoproterenol. Excess adrenaline or nor-adrenaline may give increased risk of lactic acidosis, making isoproterenol the drug of choice. TREATMENTOF HYPEROSMOLARCOMA The essence of treatment of hyperosmolar non-ketotic coma is 'moderation'. Smaller amounts of insulin are required than in the classical ketoacidotic form. The hyperosmolarity may in part be caused by hypernatraemia, so this is one situation where 77 mEq/1 saline is the replacement fluid of choice. However, slower correction of the fluid deficit is wise to reduce the risk of cerebral oedema. Potassium shifts may be rapid so that plasma potassium should be measured frequently. Thrombotic episodes in this form of coma are not uncommon (Pyke, 1969; Whelton, Walde and Havard, 1971) so that anticoagulation should be considered. Finally, this form of coma is frequently accompanied, or precipitated, by severe coexisting disease, particularly renal, cerebral or cardiac. TREATMENT OF LACTIC ACIDOSIS

Treatment remains unsatisfactory and there is a persistently high mortality. The basic aims are to eliminate the high lactate production, to facilitate removal of lactate, and to correct pH. If shock is a causative factor, an adequate circulation must be restored. Extracellular intravascular fluids will be necessary and inotropic agents should be considered. Isoproterenol is the agent of choice for it has little or no lactatogenic effect, unlike adrenaline and nor-adrenaline (Oliva, 1970). Vigorous alkalinisation with bicarbonate is necessary to overcome the depressive effects of the acidosis on ventricular contraction. Tris-hydroxy-methyl-aminomethane (THAM) has been recommended because it raises intracellular pH. Methylene blue, a redox dye, has also been used in an effort to regenerate NAD so that lactate may be converted to pyruvate and then catabolised. Neither of these treatments has met w i t h success, due presumably to the life-threatening nature of the conditions which have precipitated the lactic acidosis. Haemodialysis may be of use, particularly if phenformin is the precipitating factor. Previously, aware of the early lactate increase after insulin in patients with only mild initial elevation of lactate, we have been hesitant in recommending early or large insulin treatment in hyperglycaemic lactic acidosis (Hockaday and Alberti, 1972). Now, with evidence that high lactate values fall on treat-

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ment of ketoacidotic coma, we suspect substantial insulin therapy to be beneficial, supported where necessary with i.v. glucose. We would therefore recommend insulin in conjunction with alkali and supportive measures for the circulation. Glucose has been used successfully by Medalle, Webb and Waterhouse (1971) while Jensen, Aerenlund and Hammer (1971) and Johnson and Waterhouse (1968) have also been successful with combined glucose and insulin in phenformin-induced lactic acidosis. FUTURE DEVELOPMENTS We do not accept the widely held view that treatment of diabetic ketoacidosis as carried out in the major centres is now completely satisfactory, or that any mortality is acceptable or inevitable. The effects of different treatments on the long term progress of the patient are unknown and discounted. How can improvement come ? Electrolytes Potassium and sodium therapy have been outlined above. Suggestions regarding phosphate have also been made. However, other ions, in particular magnesium and calcium, have been largely ignored although some centres use replacement fluids containing magnesium. The fall in serum levels of Ca 2÷ on treatment is much less profound than the fall in phosphate or potassium (Martin et al, 1958). The effects of deficiencies of these ions on intracellular metabolic processes is largely conjectural. A study of this in experimental animals and man is necessary. It is known, for instance, that repair of a potassium deficit in the presence of magnesium deficiency is less beneficial for myocardial function than repair of both deficits simultaneously. This may well apply to other systems. We are also ignorant of membrane function in diabetic coma. What effect does the rapid chang¢ of transcellular electrolyte and membrane gradients have on cellular function, in particular in the central nervous system ? Do the usual properties of the cellular membrane still obtain at low pH ? is the loss of consciousness a result of ionic change, of cellular dehydration or of impaired neuro-transmitter release and function ? Cardiovascular function. Hypotension is a severe clinical problem and may worsen with treatment. A knowledge &myocardial function and control of peripheral flow in different metabolic states is required. It is obviously inappropriate to improve blood pressure entirely by arteriolar vasoconstriction if this is going to result in decreased tissue perfusion. Detailed studies of distribution of blood flow are necessary. Metabolic inhibitors The complexity of the metabolic aberrations present in ketoacidosis is obvious. What we do not know is the best method for correction so that all features are smoothly and simultaneously returned to normal with no secondary inbalances developing.

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Our own studies suggest accelerated lipolysis continues despite adequate correction of hyperglycaemia, resulting probably from sustained high levels of the anti-insulin hormones cortisol, glucagon and catecholamines. D6rot (1971) showed that this could be overcome by nicotinic acid. Other antilipolytic agents also need testing. As cortisol also has an intense catabolic and gluconeogenic effect it would be of value to study the effects of partial blockade of adrenocorticoid release. We are also ignorant of the effect of these different forms of treatment on blood/CSF metabolite exchange. Present evidence suggests much more sluggish and sometimes discrepant alterations in C.S.F. than in blood. Insulin

There are still widespread differences of practice in the amounts of insulin given, its frequency, and the route of administration. This surely bespeaks ignorance of the most effective therapy. Intravenous insulin has a half life of less than 15 minutes. Intramuscular and subcutaneous insulin are dependent on effective tissue perfusion for removal. The usual practices of mixed intravenous and intramuscular or intermittent intravenous insulin will result in a 'roller-coaster' effect on plasma le.vels with resultant uneven correction of metabolitic defects. It seems rational to use a continuous intravenous infusion of insulin, much smaller doses being required. One must remember however that insulin adheres readily to glass and synthetic materials unless protein is present, so that it should be given in 1 to 5 per cent human albumin. In summary, the treatment of diabetic coma contains myriad pitfalls for the unwary. Constant observation, flexibility of approach to cope with lifethreatening coexistent conditions, and close attention to detail are required. However, excellence in clinical care must not substitute entirely for the evolution through logic and experience of new forms of therapy. REFERENCES

Abrahamson, E. & Arky, R. (1966) Diabetic acidosis with initial hypokalaemia. Journal of the American Medical Association, 196, 401-403. Alberti, K. G. M. M. et al (1972b) Tissue oxygenation in diabetic coma. Paper presented to the European Association for the Study of Diabetes, Madrid, Sept. 1972. Alberti, K. G. M, M. et al (1972c) Red cell 2,3-diphosphoglycerate and tissue oxygenation in uncontrolled diabetes. Lancet, in press. Alberti, K. G. M. M. & Hockaday, T. D. R. (1972a) Rapid blood ketone body estimation in the diagnosis of diabetic ketoacidosis. British Medical Journal, ii, 565-568. Alberti, K. G. M. M. & Hockaday, T. D. R. (1972b) Blood lactic and pyruvic acids in diabetic coma. Diabetes 21, Suppl. 1,350. Alberti, K. G. M. M. & Hockaday, T. D. R. (1972c) Serum growth hormone in diabetic coma. Diabetologia. In press. Alberti, K. G. M.M. et al (1972a) Metabolic changes in active chronic hepatitis. Clinical Science. 42, 591-605. Arieff, A, I. & Carroll, H. J. (1971) Hyperosmolar non-ketotic coma with hyperglycaemia: Abnormalities of lipid and carbohydrate metabolism. Metabolism, 20, 529-538. Asfeldt, V. H. (1965) Ketoacidosis diabetica. A prognostic and therapeutic study of 119 consecutive cases. Danish Medical Bulletin, 12, 103-111.

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Astrup, P. (1970) Dependence of oxyhaemoglobin dissociation and intraerythrocytic 2,3-DPG on acid-base status of blood. II. Clinical and experimental studies. Advances in Experimental Medicine and Biology, 6, 67-79. Bagdade, J. D., Porte, D. Jr & Bierman, E. L. (1967) Diabetic lipaemia: A form of acquired fat-induced lipaemia. New England Journal of Medicine, 276, 427-433. Balasse, E., Couturier, E. & Franckson, J. R. M. (1967) Influence of sodium 13-hydroxybutyrate on glucose and free fatty acid metabolism in normal dogs. Diabetalogia, 3, 488-493. Bates, M. W., Krebs, H. A. & Williamson, D. H. (1968) Turnover rates of ketone bodies in normal, starved and alloxan-diabetic rats. Biochemical Journal, 110, 655-661. Bellingham, A. J., Detter, J. C. & Lenfant, C. (1971) Regulatory mechanisms of haemoglobin oxygen affinity in acidosis and alkalosis. Journal of Clinical Investigation, 50, 700-706. Bellingham, A. J., Detter, J. C. & Lenfant, C. (1970) The role of haemoglobin oxygen affinity and red cell 2,3-DPG in the management of diabetic ketoacidosis. Transactions of the Association of American Physicians, 83, 113-120. Benesch, R. & Benesch, R. E. (1967) The effect of organic phosphates from the human erythrocyte on the allosteric properties of hemoglobin. Biochemical and Biophysical Research Communications, 26, 162-167. Bergstrom, J., Hultman, E. & Roch-Norlund, A. (1969) lntraven6s fructostillf6rsel kan vara livsfarlig. Liikartidningen, 66, 2223-2229. Berry, M. N. (1967) The liver and lactic acidosis. Proceedings of the Royal Society of Medicine, 60, 1260-1262. Bingle, J. P. et al (1971) Education of diabetic patients. British Medical Journal, iv, 745. Bondy, P. K. (1971) Disorders of carbohydrate metabolism. In Textbook of Medicine, ed. Beeson, P. B. & McDermott, W., pp. 1639-1664. Philadelphia and London: Saunders. Bradley, R. F. (1971) Diabetic ketoacidosis and coma. In Joslin's Diabetes Mellitus, ed. Marble, A., White, P., Bradley, R. F. & Krall, L. P., pp. 361-416. Philadelphia: Lea and Fabiger. Bradley, R. F. & Rees, S. B. (1963) Water, electrolyte and hydrogen abnormalities in diabetes mellitus. In Clinical Metabolism of Body Water and Electrolytes, ed. Bland, J. H., pp. 408-467. Philadelphia: W. B. Saunders. Brosnan, J. T., Krebs, H. A. & Williamson, D. H. (1970) Effects of ischaemia on metabolite concentrations in rat liver. Biochemical Journal, 117, 91-96. Butler, A. M. (1950) Diabetic coma. New England Journal of Medicine, 243, 648-659. Butler, A. M. et al (1947) Metabolic studies in diabetic coma. Transactions of the Association of American Physicians, 60, 102-109. Chanutin, A. & Curnish, R. R. (1967) Effect of organic and inorganic phosphates on the oxygen equilibrium of human erythrocytes. Archives of Biochemistry and Biophysics, 121, 96-102. Chase, L. A. (1927) Diabetic lipaemia retinalis with report of a case. Canadian Medical Association Journal, 17, 197-204. Clements, R. S. et al (1971) Increased cerebro-spinal fluid pressure during treatment of diabetic ketosis. Lancet, ii, 671-675. Clementsen, H. J. (1962) Potassium therapy--a break with tradition. Lancet, ii, 175177. Cryer, P. E. & Daughaday, W. H. (1970) Diabetic ketosis. Serial growth hormone concentration during therapy. Diabetes, 19~ 519-523. Dauchy, F. et al (•970) Evolution du glucose des acides gras, et du glyc6rol dans 10 acidoc6toses diabetiques graves trait6es. Gazette Medicale de France, 77, 2653-2658. Daughaday, W. H. (1958) The nature and correction of diabetic ketoacidosis. Diabetes, 7, 230-235. D6rot, M. (1971) Severe diabetic keto-acidosis. Claude Bernard Lecture presented at the 7th annual meeting of the European Association for the study of Diabetes. Sept, 1971, Southampton.

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Ditzel, J. (1971) Changes in rheology and oxygen transport function of the erythrocyte in diabetes. In Microcirculatory Approaches to Current Therapeutic Problems. Symposia. 6th European Conference on Mierocirculation, Aalborg, 1970. p. 123-131. Basel :Karger. Duncan, L. J. P. (1971) In Textbook of Medical Treatment, 12th edition, ed. Macgregor, A. C. & Girdwood, R. H., p. 332-335. Edinburgh & London: Churchill Livingstone. Elkinton, J. R., Winkler, A. W. & Danowski, T. S. (1948) Transfers of cell sodium and potassihm in experimental and clinical conditions. Journal of Clinical Investigation, 27, 74--81. Felig, P. et al (1970) Plasma amino acid levels in diabetic ketoacidosis. Diabetes, 19, 727-729. FitzGerald, M. G., O'Sullivan, D. J. & Malins, J. M. (1961) Fatal diabetic ketosis. British Medical Journal, i, 247-250. Gerich, J. E., Martin, M. M. & Recant, L. (1971) Clinical and metabolic characteristics of hyperosmolar non-ketotic coma. Diabetes, 20, 228-238. Glynne, A. (1970) Diabetic ketoacidosis. British Medical Journal, iv, 366. Goldfinger, S., Klinenberg, J. R. & Seegmiller, J. E. (1965) Renal retention of uric acid induced by infusion of fi-hydroxybutyrate and acetoacetate. New England Journal of Medicine, 272, 351-355. Greenbaum, A. L., Gumaa, K. A. & McLean, P. (1971) The distribution of hepatic metabolites and the control of the pathways of carbohydrate metabolism in animals of different dietary and hormonal status. Archives Biochemistry attd of Biophysics, 143, 617-633. Guest, G. M. & Rapaport, S. (1948) Electrolytes of blood plasma and cells in diabetic acidosis and during recovery. Proceedings of the American Diabetes Association, 7, 97-115. Hardwick, C. (1970) In Current Medical Treatment, 3rd edn., ed. Harvard, C. W., pp. 430-434. London: Staples Press. Harris, L. V. D. et al (1953) Serum lipids in diabetic acidosis. Metabolism, 2, 120-132. Harrop, G. A. & Benedict, E. M. (1924) The participation of inorganic substances in carbohydrate metabolism. Journal of Biological Chemistry, 59, 683-697. Hartmann, A. F. (1935) Treatment of severe diabetic acidosis. A comparison of methods with particular reference to the use of racemic sodium lactate. Archives of Internal Medicine, 56, 413-434. Harwood, R. (1951) Diabetic acidosis, results of treatment in 67 consecutive cases. New England Journal of Medicine, 245, 1-9. Hawkins, R. A. et al (1971) The effect of acetoacetate on plasma insulin concentration. Biochemical Journal, 125, 541-544. Hockaday, T. D. R. (1971) Diabetic comas. Postgraduate Medical Journal, 47, June Supplement, 376-381. Hockaday, T. D. R. & Alberti, K. G. M. M. (1972) Diabetic coma. British Journal of Hospital Medicine, 7, 183-198. Hoekaday, T. D. R., Alberti, K. G. M. M. & Wilkinson, R. H. (1972) Plasma potassium in diabetic ketoacidosis. Proceedings of the British Diabetic Association, Spring Meeting, April, 1972, York. Holler, J. W. (1946) Potassium deficiency occurring during the treatment Of diabetic acidosis. Journal of the American Medical Association, 131, 1186-1189. Howarth, S., McMichael, J. & Sharpey-Shaefer, E. P. (1948) Low blood pressure in diabetic coma. Clinical Science, 6, 247-255. Hudson, B., Bick, M. & Martin, F. I. R. (1960) Observations on the treatment of severe diabetic ketosis. Australasian Annals of Medicine, 9, 34-40. HiJther, W. (1965) Diagnostik and Therapie comat6ser Zust~indeim Kindesalter. Manchener medizinische Wochenschrift, 107, 1025-1035. Jackson, W. P. U. (1971) A critical appraisal of mechanisms concerned in non-ketotic hyperosmolar diabetic coma. Postgraduate Medical Journal (June Suppl.), 47, 371-375. Jacobs, H. S. & Nabarro, J. D. N. (1969) Plasma ll-hydroxycorticosteroid and growth hormone levels in acute medical illnesses. British Medical Journal, ii, 595-598. Jensen, H. Aerenlund & Hammer, A. (1971) Maelkesyreacidose hos diabetiker i fenforrnin behandling (Lactic acidosis in a diabetic on phenformin medication). Nordisk medicin, 85, 469-471.

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