12
Review Fa atal Diabetic Ketoacidosis: Major Causes and Approaches to Their Prevention REX S. CLEMENTS, JR. AND BHASKAR VOURGANTI W hile the actual incidence of diabetic keto- acidosis is not known, at the present time this condition accounts for roughly 14 per cent of the admissions of diabetic pa- tients to hospitals in the United States 1 and is responsible for 4-5 per cent of the deaths in the Japanese diabetic population. 2 Mortality figures collected from various medical centers during the last decade have varied from as low as 0.5 per cent to as high as 15.4 per cent with a mean mortality of 6.8 per cent in the 2,348 patients for whom adequate information is available. 1 Thus, although the mortality due to ketoacidosis has decreased from the range of 27 to 44 per cent observed between 1930 and 1950, 3 ~ 6 the survival of patient has not appeared to improve strikingly during the past 25 years. It has long been assumed that many of the deaths associated with ketoacidosis are due to coexisting medical disease such as myocardial infarction, cerebrovas- cular accident, mesenteric arterial occlusion, pancreatitis, and infection. If this were the case, the physician would have to be satisfied with attempting to prevent those deaths due to "uncomplicated" diabetic ketoacidosis and would resign himself to the loss of patients with severe complicating medical disease. 7 If, on the other hand, cer- tain of the coexisting diseases could be shown to be the consequence of diabetic ketoacidosis rather than its cause, then it would be possible to take appropriate measures to decrease the frequency of their development during the treatment of this disorder. The fact that, in certain series, the mortality associated with ketoacidosis has been zero would support the possibility that many of the so-called "unavoidable" deaths might have been prevented. It is the purpose of this discussion to examine the causes of death in patients treated for diabetic keto- acidosis and to propose therapeutic measures which might decrease the associated mortality. Since McGarry and Foster have recently reviewed the biochemical physiology of keto- acidosis, only those aspects which are pertinent to the treatment of diabetic ketoacidosis will be considered here. 8 PATHOGENESIS OF KETOACIDOSIS Ketoacidosis is the end result of a nearly absolute de- ficiency of circulating endogenous or exogenous insulin. Under normal circumstances, insulin acts to suppress the breakdown of adipose tissue triglycerides through its inhibitory effect on the adipocyte hormone-sensitive lipase system. 8 In the absence of insulin (as well as in the presence of elevated serum concentrations of cate- cholamines, cortisol, and glucagon) this lipase system is activated and catalyzes the rapid breakdown of adipose tissue triglycerides and the consequent release of their component fatty acid and glycerol moieties into the circulation. The fatty acids (which are largely bound to albumin) are carried to the liver where they readily enter the hepatocyte and are converted to their coenzyme A derivatives. The activated fatty acids have two major fates: they either can be reesterified to form triglycerides within the cytosol of the hepatocyte, or they can enter the mitochondrion wherein they are quantitatively oxidized to acetylcoenzyme A (acetyl-CoA). The rate of entry of fatty acids into the mitochondrion is determined by the enzyme carnitine acyltransferase I which is located on the outer surface of the inner mitochondrial membrane. Since this enzyme mediates the replacement of the coenzyme A moiety with a ( )carnitine molecule, its activity is regu- lated, in part, by the availability of ( )carnitine within the liver. In ketotic animals, the hepatic ( )carnitine concentration is elevated, and the entry of fatty acids into the mitochondria is therefore maximized. In addition, malonyl-CoA (in concentrations that are normally found within the hepatocyte of the fed animal) is a potent inhibitor of carnitine acyltransferase I. 10 In ketoacidosis, the hepatic malonyl-CoA concentration and its inhibition of the transferase are decreased. Glucagon is thought to play a major role in the lowering of the hepatic malonyl- CoA concentration as a result of its activation of glycogen phosphorylase and its inhibition of pyruvate kinase and 314 DIABETES CARE, VOL. 1 NO. 5, SEPTEMBER-OCTOBER 1978 Downloaded from http://diabetesjournals.org/care/article-pdf/1/5/314/437291/1-5-314.pdf by guest on 26 January 2022

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Page 1: Review Faatal Diabetic Ketoacidosis: Major Causes - Diabetes Care

Review

Faatal Diabetic Ketoacidosis:Major Causes and Approaches

to Their PreventionREX S. CLEMENTS, JR. AND BHASKAR VOURGANTI

While the actual incidence of diabetic keto-acidosis is not known, at the present timethis condition accounts for roughly 14per cent of the admissions of diabetic pa-

tients to hospitals in the United States1 and is responsiblefor 4-5 per cent of the deaths in the Japanese diabeticpopulation.2 Mortality figures collected from various medicalcenters during the last decade have varied from as low as0.5 per cent to as high as 15.4 per cent with a mean mortalityof 6.8 per cent in the 2,348 patients for whom adequateinformation is available.1 Thus, although the mortalitydue to ketoacidosis has decreased from the range of 27 to44 per cent observed between 1930 and 1950,3~6 the survivalof patient has not appeared to improve strikingly during thepast 25 years. It has long been assumed that many of thedeaths associated with ketoacidosis are due to coexistingmedical disease such as myocardial infarction, cerebrovas-cular accident, mesenteric arterial occlusion, pancreatitis,and infection. If this were the case, the physicianwould have to be satisfied with attempting to preventthose deaths due to "uncomplicated" diabetic ketoacidosisand would resign himself to the loss of patients with severecomplicating medical disease.7 If, on the other hand, cer-tain of the coexisting diseases could be shown to be theconsequence of diabetic ketoacidosis rather than its cause,then it would be possible to take appropriate measuresto decrease the frequency of their development duringthe treatment of this disorder. The fact that, in certainseries, the mortality associated with ketoacidosis hasbeen zero would support the possibility that many of theso-called "unavoidable" deaths might have been prevented.It is the purpose of this discussion to examine thecauses of death in patients treated for diabetic keto-acidosis and to propose therapeutic measures which mightdecrease the associated mortality. Since McGarry and Fosterhave recently reviewed the biochemical physiology of keto-acidosis, only those aspects which are pertinent to thetreatment of diabetic ketoacidosis will be considered here.8

PATHOGENESIS OF KETOACIDOSIS

Ketoacidosis is the end result of a nearly absolute de-ficiency of circulating endogenous or exogenous insulin.Under normal circumstances, insulin acts to suppressthe breakdown of adipose tissue triglycerides throughits inhibitory effect on the adipocyte hormone-sensitivelipase system.8 In the absence of insulin (as well as inthe presence of elevated serum concentrations of cate-cholamines, cortisol, and glucagon) this lipase system isactivated and catalyzes the rapid breakdown of adiposetissue triglycerides and the consequent release of theircomponent fatty acid and glycerol moieties into thecirculation. The fatty acids (which are largely bound toalbumin) are carried to the liver where they readilyenter the hepatocyte and are converted to their coenzymeA derivatives. The activated fatty acids have two majorfates: they either can be reesterified to form triglycerideswithin the cytosol of the hepatocyte, or they can enter themitochondrion wherein they are quantitatively oxidizedto acetylcoenzyme A (acetyl-CoA). The rate of entry offatty acids into the mitochondrion is determined by theenzyme carnitine acyltransferase I which is located on theouter surface of the inner mitochondrial membrane. Sincethis enzyme mediates the replacement of the coenzyme Amoiety with a ( — )carnitine molecule, its activity is regu-lated, in part, by the availability of ( — )carnitine withinthe liver. In ketotic animals, the hepatic ( — )carnitineconcentration is elevated, and the entry of fatty acids intothe mitochondria is therefore maximized. In addition,malonyl-CoA (in concentrations that are normally foundwithin the hepatocyte of the fed animal) is a potentinhibitor of carnitine acyltransferase I.10 In ketoacidosis,the hepatic malonyl-CoA concentration and its inhibitionof the transferase are decreased. Glucagon is thought toplay a major role in the lowering of the hepatic malonyl-CoA concentration as a result of its activation of glycogenphosphorylase and its inhibition of pyruvate kinase and

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acetyl-CoA carboxylase.11 The combination of increasedfatty acyl-CoA and (— )carnitine concentrations as well as thedecreased malonyl-CoA concentration is thought to permitmaximal rates of transfer of fatty acids into the mitochondriawhere they can be rapidly converted to acetyl-CoA.

A large fraction of the acetyl-CoA which is generatedwithin the mitochondrion is converted to acetoacetate, theparent ketoacid. Since mitochondrial nicotine adeninedinucleotide is reduced during the oxidation of fattyacids, and since betahydroxybutyrate dehydrogenase is anequilibrium enzyme, the majority of the acetoacetateproduced under these conditions is converted to betahydroxy-butyrate. The liver lacks the capacity to utilize theseketoacids and consequently they are released into thesystemic circulation. It is estimated that under conditionsof maximal rates of ketogenesis, the adult human liver iscapable of producing approximately 50 mEq. of ketoacidsper hour. The resultant acid load promptly overpowersthe body's buffering systems and leads to acidosis. Thesteady-state serum concentrations of ketoacids achieved insevere ketoacidosis reflect not only the rapid rate of hepaticketogenesis, but also the decreased rates of their peripheraldisposal and urinary excretion.

Concurrent with the increased rate of ketogenesis,hepatic gluconeogenesis is also increased three- to fourfoldin insulin deficiency states. This is due not only to in-creased activity of the hepatic enzymes peculiar togluconeogenesis, but also to increased substrate provisionto and uptake by the liver. The resultant outpouring ofglucose by the liver produces hyperglycemia, which isfurther aggravated by decreased peripheral glucose utiliza-tion and eventually by decreased urinary glucose excre-tion. The osmotic diuresis resulting from the urinaryexcretion of glucose and ketoacids results in the loss ofwater and electrolytes. If not corrected, such losses willeventuate in hypovolemia, hypotension, and death.

CAUSES OF DEATH DURING TREATMENT OF DIABETIC KETOACIDOSIS

Although it is difficult to determine the precisecause of death in patients who die during orshortly after treatment for diabetic ketoacidosis,analysis of the presumed causes of death among

the representative 3,307 patients described in references3-6 and 12-36 reveals some interesting facts. First, ashas been noted in the past, the mortality due to diabeticketoacidosis during the past three decades is considerablylower than that observed between 1930 and 1959 (table 1).

InfectionsIn recent years, fewer patients have been observed topresent with ketoacidosis following an infection, andtherefore it is not surprising that the percentage of patients

TABLE 1Causes of death in 3,007 patients treated for diabetic ketoacidosis beforeand after the year 1960

Time period

1930-19591960-present

No. ofcases

1,5381,769

Mortality

389

Major factor responsible

Infection

4125

Arterialthrombosis

2533

for death

Shock

2838

whose death was attributed to infection has declined. Al-though patients continue to enter the hospital in a moribundstate with obvious but untreatable infections, at the presenttime most fatal infections appear to develop after the insti-tution of therapy and lead to death several days or weeksafter admission. Thus, with the exception of those patientswhose condition is hopeless from the outset, appropriate localand antibiotic therapy might decrease the mortality asso-ciated with infection. It should be stressed that infectionleads to death in only 2 per cent of patients treated fordiabetic ketoacidosis, and consequently it is no longerrational to provide indiscriminate broad-spectrum anti-biotic coverage for all patients.16 On the other hand,in every instance it is imperative that a thorough searchfor a site of infection should be carried out and appro-priate therapy be promptly instituted if infection is suspected.

Vascular ThrombosesDeath due to arterial thrombosis is a common and rela-tively constant cause of death in patients with diabeticketoacidosis (table 1). Virtually all muscular arteries maybe involved (carotid, coronary, mesenteric, iliac, renal,splenic, and pancreaticoduodenal). In general, the afflictedpatient enters the hospital with "uncomplicated" keto-acidosis and develops evidence of an arterial occlusionseveral hours or days after the institution of therapy.Commonly, the thrombosis supervenes after the biochemicalcorrection of ketoacidosis has been achieved. In the past,physicians have been tempted to consider major arterialocclusions as the precipitating causes of diabetic keto-acidosis and have included the resultant fatalities underthe rubric of "unavoidable deaths." However, the timecourse of the development of these vascular disasters as wellas our increasing knowledge of the disorders of the coagula-tion and circulatory systems in diabetic ketoacidosis wouldsuggest that they may be the direct result of both keto-acidosis and the treatment thereof. If this is the case, cer-tain of these vascular complications might be prevented byappropriate therapeutic measures.

A number of phenomena probably interact to increase thepropensity of the patient in diabetic ketoacidosis to develop

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vascular thromboses. First, he is profoundly dehydrated andhas a markedly contracted intravascular volume.37"39 Second,the viscosity of his blood is increased (in part due to ele-vated serum globulins).40'41 Thirdly, his cardiac output maybe profoundly decreased due to the concurrent acidosis.42

Finally, he may have compromised circulatory dynamics dueto preexisting premature atherosclerosis as well as to auto-nomic neuropathy. All of these abnormalities could lead toimpaired general or regional delivery of blood. Despitethese theoretical abnormalities in the circulatory system, theblood flow to the brain and forearm of the patient inketoacidosis has been found to pe normal during the earlystages of ketoacidosis.43'44 Consequently, if we are searchingfor causes of delayed thromboses, we must consider additionalfactors. It is well known that the platelets of the uncon-trolled diabetic patient are abnormally adhesive and are un-usually sensitive to factors which promote platelet aggre-gation.45'46 Increased Factor VIII and fibrinogen levels as wellas decreased fibrinplysis have also been described in diabeticpatients.47'48 Platelet aggregates have been observed innumerous muscular arteries (in particular, the small andmedium-sized cerebral arteries) of a surprising proportion ofpatients who die as a result of ketoacidosis.49 Conse-quently, the combination of impaired regional blood flowwith these defects in the control of coagulation couldcontribute to the development of thromboses in suchpatients. Another preexisting hematologic disorder whichcould contribute to thrombogenesis is the high percentageof glycosylated hemoglobin in the erythrocytes of the un-controlled diabetic patient.50 Since glycosylated hemoglobindoes not increase its release of oxygen to the tissues as a resultof interaction with the erythrocyte 2,3-diphosphoglycerate(2,3-DPG), this might result in a slight impairment inthe delivery of oxygen to the tissues of the ketoacidoticdiabetic.51 This phenomenon might also explain, in part,the decreased oxygen uptake of the brain which has beendocumented in ketoacidotic patients.43 The resultant tissuehypoxia could, in turn, interact with the impaired bloodflow and the hypercoagulable state to induce thromboses.

However, although the aforementioned abnormalitieswould be expected to set the stage for the formation ofarterial thrombi, they do not provide an explanation for thefact that thrombi usually develop after the institutionof therapy and are uncommonly observed in the un-treated patient. Consequently, we must look upon thosefactors which develop during the course of treatment asprimary actors in this particular drama. First, as will bediscussed in more detail later, one of the objectives of thetreatment of diabetic ketoacidosis is to lower the plasmaglucose concentration by means of insulin and fluid therapy.Since, at the outset, the size of the extracellular andintravascular fluid spaces is maintained in part by theosmotic effect of the elevated plasma glucose concentra-

tion, a therapeutic lowering of the circulating glucoseconcentration would tend to decrease the intravascularand extracellular fluid volumes. In a patient who has al-ready lost 10 per cent of his body weight in the form offluid, any additional decrease in his intravascular volumewould further increase his blood viscosity and decreasehis ability to supply oxygen to the tissues. The resultantdecrease in cardiac output may play a major role in theprecipitation of both hypovolemic shock and thrombo-genesis. In support of this speculation is the observationthat the peripheral blood flow (which may be normal at theoutset) decreases following insulin treatment.44

In addition, the tissue hypoxia resulting from the inter-actions between erythrocyte 2,3-DPG, arterial blood pH, andhemoglobin during the treatment of ketoacidosis couldalso play a role in the delayed development of arterialocclusions.52'53 It has been well established that the 2,3-DPGconcentrations are extremely low in the erythrocytes ofthe patient in diabetic ketoacidosis.52'53 Since 2,3-DPGpromotes the delivery of oxygen from the hemoglobinmolecule to the tissues, such a decrease in the erythrocyte2,3-DPG concentration would be expected to impair tissueoxygenation. However, in the untreated patient with keto-acidosis, this effect is counterbalanced by the concurrentacidosis.52'53 It is only when the physician enters the sceneand attempts to correct the acidosis by means of insulinand bicarbonate therapy that the abnormal oxyhemoglobindissociation is unmasked. Thus, one would anticipate that,as the arterial blood pH of the patient is raised duringthe course of treatment, his tissue oxygenation would falland his susceptibility to vascular thrombosis would increase.Furthermore, since it takes approximately a week to restorethe erythrocyte 2,3-DPG concentrations to normal, onewould predict that the patient would continue to be at riskfor the development of vascular occlusions for several daysfollowing the successful treatment of diabetic ketoacidosis.53

Finally, the observation that the intravenous administra-tion of insulin accelerates the aggregation of platelets inthe diabetic subject raises the possibility that insulinadministration could play a direct role in the developmentof intravascular coagulation during the treatment of keto-acidosis.54

ShockIn recent years, hypovolemic shock appears to have beenresponsible for an increasing proportion of deaths due toketoacidosis (table 1). However, the extent of this increasemay be greater than the data indicate, since many of thedeaths attributed to shock in the early days of insulintherapy may have been due to unsuspected hypoglycemiaor hypokalemia. Furthermore, in certain series, virtuallyall "unexplained" deaths have been attributed to hypo-volemic shock.21'34 The importance of severe hypovolemia

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as a major contributing factor to the death of patientstreated for ketoacidosis is highlighted by Beigelman's re-cent observation that severe intravascular volume depletionwith resultant hypotension, anuria, hyperosmolality, andazotemia is the major prognostic index for a subsequentunfavorable therapeutic outcome.25

As with vascular occlusions, death due to shock com-monly occurs after several hours or days of treatment.As mentioned earlier, the decreased intravascular volumedue to hypotonic fluid losses and the impaired cardio-vascular function due to acidosis could obviously con-tribute to the development of irreversible hypovolemicshock. However, it is equally important to consider thoseiatrogenic factors which might precipitate the develop-ment of this calamity in the predisposed patient.

First, let us consider the effect of our treatment regimenson the volumes of the intracellular and extracellular fluidspaces. As mentioned earlier, the patient in severe keto-acidosis has lost nearly 10 per cent of his body weight inthe form of fluid (the composition of which is roughlyequivalent to 0.45 per cent sodium chloride with 15 to 30mEq. per liter of potassium chloride)..37 Roughly one half ofthis fluid is lost from the intracellular and one half fromthe extracellular fluid space.37 On admission, the extra-cellular fluid space is partially maintained by the osmoticcontribution of the extracellular fluid glucose concentra-tion (1 mosmol. per kilogram is contributed for each 18mg. per deciliter of glucose). If the plasma glucose isabruptly decreased, water will move from the extracellularfluid space into the cells. The resultant decrease in the intra-vascular volume might be sufficient to precipitate irreversibleshock in the susceptible patient.

To illustrate the fluid shifts that can occur during thetreatment of diabetic ketoacidosis, as well as the effect of thecomposition of the intravenously administered fluids on suchshifts, we have presented in table 2 some data on a patientwhom we recently studied. This patient was a young man,19 years of age, who had been known to have insulin-requiring diabetes mellitus for 12 years and who had de-veloped ketoacidosis three days after having discontinuedhis insulin treatment. On admission his plasma glucose

was 567 mg. per deciliter and his arterial blood pH was 6.97.He was treated with an intravenous bolus of 0.15 U. perkilogram body weight of regular insulin followed by 0.15 U.per kilogram body weight of insulin per hour by constantintravenous infusion. He received approximately 500 ml. perhour of isotonic saline and put out a total of 1,200 ml. ofurine during the first four hours of treatment. It was estimatedthat he had lost a total of six liters of fluid during thedevelopment of ketoacidosis and that his extracellular fluidspace had decreased to 11 liters before the initiation oftreatment (14 liters would nave been normal for his bodyweight). After four hours of treatment, his plasmaglucose had fallen to 101 mg. per deciliter, and glucose-containing fluids were added to his treatment regimen. Intable 2, the calculated serum osmolality, serum sodium, andintra- and extracellular fluid volumes are shown beforetreatment as well as after four hours of administrationof either two liters of isotonic saline (his actual treatment),four liters of isdtonic saline (a theoretical treatment), or twoliters of 0.45 per cent saline (a theoretical treatment). Forthe purpose of these calculations, it was assumed thatuilder all treatment regimens he would have excreted1,200 ml. of urine which contained 77 mEq. per liter ofNaCl and 20 mEq. per liter of KC1. As can be seen, whentwo liters of isotonic saline was administered, there was arise in both the serum osmolality and the serum sodium.The calculated rise in his serum sodium concentration (6.4mEq. per liter) is slightly less than the theoreticalrise in serum sodium derived from the formula of Katz(7.5 mEq. per liter) due to his urinary sodium losses.55

Of the 800 ml. of fluid retained, all of it remained withinthe extracellular fluid space, and an additional 300 ml. wascontributed to the extracellular fluid space at the expense ofcell water. In contrast, following the administration ofhypotonic fluids, the serum osmolality would have de-creased and the serum sodium would have risen slightly.Only half of the retained fluid (400 ml.) would have re-mained in the extracellular space and the remainder wouldhave entered the cells. If we had doubled the rate ofisotonic saline administration, we would have observed aslightly greater rise in the serum sodium, a lesser rise of

TABLE 2Calculation of the changes in serum osmolality, serum sodium, and intracellular and extracellular fluid volumes in a 19-year-old patient treated fordiabetic ketoacidosis with insulin and either isotonic or hypotonic saline administration

Plasmaglucose

(mg./dl.)

Serumosmolality

(mosmol./kg.)

Serumsodium

(mEq./liter)

Extracellularfluid volume

(liters)

Intracellularfluid volume

(liters)

Before therapyAfter four hours of therapy (2,000 ml. of isotonic saline)After four hours of therapy (2,000 ml. of 0.425% saline)After four hours of therapy (4,000 ml. of isotonic saline)

567101101101

311.5315.5307.1315.1

140.0146.4141.8147.4

11.012.111.414.1

25.024.725.424.7

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his osmolality, and a restoration of the extracellular fluidspace to normal.

If the initial objective of intravenous fluid administrationis to restore the intravascular volume in order to increasecardiac output and to permit the delivery of blood to thetissues, it is apparent that equivalent amounts of 0.425 percent saline are only 40 per cent as effective as isotonic salinein achieving this goal and that rapid rates of isotonic salineadministration are required to restore the intravascularvolume as promptly as possible. This observation supportsthe recent suggestion of Feig and McCurdy that hypotonicfluids should be used with caution in the treatment of patientswho are severely sodium depleted and that isotonic fluidsare preferable.56 Although we are not suggesting that theeventual restoration of the intracellular volume is not desir-able, we wish to emphasize that the first objective in thefluid therapy of the ketoacidotic diabetic should be to re-plete the intravascular volume. It is apparent that theearly use of isotonic fluids is more likely to permit theachievement of this goal than is the use of hypotonicfluids during the early phase of treatment.

A second mechanism which may be of pathophysiologicimportance in the delayed development of shock is relatedto the aforementioned abnormalities in the erythrocyte 2,3-DPG concentrations. When the acidotic patient is treatedwith fluids, insulin, and bicarbonate, the resultant increasein blood pH will lead to a left-shift of the oxyhemo-globin dissociation curve which will decrease the delivery ofoxygen to the tissues.43'53 In order to compensate forthe resultant tissue hypoxia, it has been estimated that thecardiac output would have to increase by three- to fourfold.52

Obviously, the combination of hypovolemia and impairedmyocardial function (secondary to acidosis), as well as thepossible additive effects of underlying cardiovasculardisease and autonomic neuropathy, might render suchcompensation impossible. Thus, it is not surprising that acertain proportion of patients treated for diabetic keto-acidosis will develop overt hypovolemic shock or left ven-tricular failure during the course of therapy.

Cerebral EdemaIn series which consist almost entirely of adults, the de-velopment of cerebral edema as a consequence of thetreatment of ketoacidosis is uncommon.25 However, fatalacute cerebral edema is not infrequently observed in pa-tients who are under the age of 25 years.57"60 As withboth vascular thromboses and shock, cerebral edema developssome hours after the initiation of therapy and is usuallyfatal.60

The mechanism responsible for the development of thiscomplication is unknown. Experiments in animals havedemonstrated that a rapid lowering of the blood glucoseconcentration after a four-hour period of hyperglycemiaconsistently results in brain swelling in both the dog61

and the rabbit.62 Although direct measurement of cere-brospinal fluid pressure has suggested that most adults developpathologic increases in intracranial pressure during thetreatment of diabetic ketoacidosis, such studies have not beenperformed in children.63 Although it was proposed thatalterations in the sorbitol content of the brain couldcontribute to the development of brain swelling follow-ing rehydration,61 the osmotic contribution of the sorbitolaccumulation within the brain is not adequate to accountfor this phenomenon.62 Alternative mechanisms that havebeen discounted include cerebral anoxia, disequilibriumbetween the pH of brain and blood, and a breakdown ofthe blood-brain barrier.62 Mechanisms which remain plausi-ble are that (1) insulin exerts a direct effect on the sodiumand potassium content of the brain, (2) the osmoticdisequilibrium produced by a slow dissipation of brain"idiogenic osmoles" leads to an increase in brain water,or (3) that a slower decrease in the brain and cerebrospinalfluid glucose concentrations during treatment generatesosmotic disequilibrium.62

DIAGNOSTIC AND THERAPEUTIC CONSIDERATIONS

DiagnosisIn all series, delayed diagnosis of diabetic ketoacidosishas been found to increase the likelihood of a fatal out-come. Therefore, in order to decrease the mortality asso-ciated with this disorder, a high index of suspicion andprompt establishment of the diagnosis are of primary im-portance. Once the diagnosis is suspected, confirmationcan be obtained within two minutes with the assistance ofDextrostix and Acetone Test powder or crushed Acetesttablets.64 Since the combination of hyperglycemia andhyperketonemia is virtually pathognomonic of diabeticketoacidosis, there is no need to await laboratory con-firmation of the presence of hyperglycemia and acidosisbefore the institution of insulin and fluid therapy.

It has been suggested that a quantitative estimate of theconcentrations of acetoacetate and betahydroxybutyratecan be achieved by the reactivity of serial dilutions ofserum with the nitroprusside reagent.65 However, sincethis reagent does not react with the predominant cir-culating ketoacid (betahydroxybutyrate), since the ratiobetween acetoacetate and betahydroxybutyrate is variable,and since the presence of acetone will contribute to thenitroprusside reaction, we have not found this method to beof any practical value in either the establishment of thediagnosis or in monitoring the effectiveness of treatmentof ketoacidosis66'67 (figure 1). However, it has been ourexperience that when the nitroprusside reaction is stronglypositive with diluted serum or plasma, ketonemia andketonuria may persist for hours after the correction of themeasurable biochemical abnormalities. The explanation for

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539

J «— Insulin administration

o—o Plasma acetone•—• Blood acetoacetateD—a Blood betahydroxybutyrate

Blood glucose

0 4 8 12 16 20 24

Hours after initiation of therapy

FIG. 1. Changes in the plasma acetone, blood acetoacetate, bloodbetah^drox^butyrate, and blood glucose during the treatment of diabeticketoacidosis. (Data recalculated from reference 92, figures 5 and 6.)This data shows the not uncommon rise in both acetone and aceta'acetate after the initiation of treatment, the gradual fall in the plasmaacetone during the first 24 hours of therapy, and the parallel decreasesin the blood betahydroxybutyrate and glucose during treatment.

this phenomenon may be that acetone (which is excretedvery slowly) is a major contributor to the initial nitro-prusside reaction in those particular patients.66 If this werethe case, one would anticipate that such patients wouldhave an obvious odor of acetone in their expired air,and that simply smelling their breath at the outset wouldpermit the physician to predict which patients would belikely to have persistent ketonuria.

Insulin TherapySince diabetic ketoacidosis is the result of the loss of theability of the pancreas to secrete insulin,68 restoration of anormal circulating insulin concentration is one of the essen-tial elements in the treatment of this disorder. Numerousschemes have been proposed to achieve this goal, andwhen properly employed, they are all equally effective inthe correction of the metabolic abnormalities.66 The majorobjectives of insulin administration are to decrease hepaticgluconeogenesis and to inhibit lipolysis. Inhibition of lipolysisis maximal at a serum insulin concentration of 40 /xU. permilliliter,69 whereas inhibition of hepatic gluconeogenesisrequires a somewhat lower circulating insulin concentra-tion.70 In contrast, a maximal effect of insulin upon theuptake of glucose by human muscle is not achieved untilplasma insulin concentrations as high as 300 /xU. permilliliter are achieved.71 Thus, if insulin administrationresults in circulating insulin concentrations of greaterthan approximately 40 /uU. per milliliter, gluconeogenesis,lipolysis, and ketogenesis will be inhibited, whereas the

uptake of glucose by the peripheral tissues will not beaffected until unphysiologically high insulin concentrationsare reached.

It is, therefore, not surprising that any route of insulinadministration (be it subcutaneous, intramuscular, intra-venous bolus, or constant intravenous infusion) whichprovides a physiologic circulating insulin concentrationwill be effective in the treatment of most cases of diabeticketoacidosis. This fact has led to the recent popularityof "low-dose" insulin treatment regimens. Although thisform of insulin therapy has been employed for over 30years,72 the recent flurry of interest in the English-speak-ing countries was sparked by a series of papers that ap-peared in the British medical literature between 1972and 1974.26'28'29.73,74 Since that time, there has been analmost continuous stream of articles confirming the effec-tiveness of low-dose insulin treatment regimens in the handsof other investigators.30"36'75"87 It is now apparent that"high-physiologic" insulin concentrations can be achievedfollowing the intravenous or intramuscular administrationof low doses of insulin and that the achievement ofsuch levels is more rapid when the intravenous route ischosen.26'28'29'85 The advantages and disadvantages of thevarious forms of low-dose insulin therapy have recently beensummarized.88 The consensus is that low-dose insulin ad-ministration is a simple and effective method for thetreatment of diabetic ketoacidosis.88 There is no convincingevidence that this technique differs from high-dose insulintherapy regimens with regard to the rate of fall of theblood glucose, the rate of correction of acidosis, theretention of potassium during therapy, or the frequencyof development of cerebral edema.88 The disadvantagesof intravenous insulin administration are that the intra-venous line must be intact, that an infusion pump isrequired for the quantitative administration of insulin,that albumin must be present in the insulin-contain-ing fluids to avoid the adsorption of variable amounts ofinsulin to the glass and tubing, and that it is ineffectivein patients with significant insulin resistance.89'90 The ad-vantages of this form of therapy are its simplicity, its usualeffectiveness, and the avoidance of late hypoglycemia. Thus,we believe that the advantages outweigh the disadvantages.

Currently, we administer an intravenous bolus of insulinat the outset (0.15 U. per kilogram normal body weight)followed by the continuous intravenous infusion of an equalamount of insulin per hour. The rate of administrationis controlled by a constant infusion pump and adsorp-tion of insulin to the infusion apparatus can be pre-vented by the addition of human serum albumin (0.4per cent) to the infusion fluids. For simplicity, we ad-minister insulin with the rehydration fluids, althoughothers may prefer to give these two forms of therapyseparately. The advantage gained by the separate adminis-tration of insulin by a syringe pump is that when the

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syringe and infusion tubing are adequately rinsed with theinsulin-containing solution before use, the addition of al-bumin to the infusate can be avoided. The blood glucoseis determined hourly, and the rate of insulin administra-tion is doubled each hour if a fall in the blood glucoseis not obtained. Once the blood glucose has fallen to 250mg. per deciliter or lower, glucose is added to theintravenous fluids. In most patients, this scheme willlower the blood glucose to <250 mg. per deciliter withinfour hours and permit the correction of acidosis within 6 to12 hours. In one patient with subsequently documentedinsulin resistance, we recently observed that the rate ofinsulin infusion had to be increased to 0.6 U. per kilogramper hour to correct the metabolic abnormalities. Thefrequent determination of the blood glucose concentrationduring the first few hours of therapy permits the rapidadjustment of the rate of insulin administration wheninsulin resistance is encountered (e.g. the proper rate ofinsulin infusion was achieved within three hours in theaforementioned patient).

Fluid and Electrolyte TherapyOne of the most valuable lessons to have been derivedfrom the recent studies of low-dose insulin therapy is thatmost patients in ketoacidosis are not resistant to the ef-fects of insulin. What is not generally appreciated,however, is that in virtually all of these studies largeamounts of isotonic fluids were administered during theearly phases of treatment (0.6 to 1.0 liters per hour). It isparticularly instructive to note that among the 38 patientsdescribed by Page et al., the blood glucose fell with re-hydration alone in all but five patients.28 Furthermore,in roughly 80 per cent of these patients, the addition ofinsulin to the treatment regimen had no appreciable effecton the rate of fall of the blood glucose. Thus, it wouldappear that rehydration, rather than an effect of insulinon peripheral glucose utilization may be of more importancein the correction of hyperglycemia. Since the normal kid-ney functions as an "escape valve" and (in the absence ofsignificant dehydration) will not permit the plasma glucoseto rise above about 200 mg. per deciliter, it is reasonableto suspect that the hyperglycemia associated with keto-acidosis is due in large part to a decrease in renal bloodflow.56 Conversely, when the ketoacidotic patient is re-hydrated and renal blood flow is reestablished, it can beanticipated that a rapid loss of glucose in the urine wouldpromptly lower the plasma glucose into the range of 200mg. per deciliter.

This speculation is somewhat heretical, since most physi-cians would prefer to believe that the lowering of the bloodglucose during the treatment of diabetic ketoacidosis is dueto insulin-mediated enhancement of peripheral glucoseutilization rather than simply to the loss of glucose in theurine.7 To localize the disposition of glucose during the

treatment of ketoacidosis, we have employed the primed-constant infusion of [3-3H]glucose (10 /u-Ci. as a bolusfollowed by 10 jotCi. per hour) during the early phase oftreatment in three patients. The formulas for non-steady-state, time-variable conditions were employed to determinethe relative contributions of hepatic gluconeogenesis,peripheral uptake, and urinary excretion to the changes inthe extracellular fluid glucose pool during recovery fromdiabetic ketoacidosis.91 The data from one of these studiesare presented in table 3. The patient is the same 19-year-old man described in the discussion of table 2.

After four hours of treatment with insulin (0.15 U. perkilogram as an intravenous bolus followed by 0.15 U. perkilogram per hour by continuous intravenous infusion) andisotonic saline (500 ml. per hour), his plasma glucosehad fallen from 567 to 101 mg. per deciliter. Themean rate of fall was 116.5 mg. per deciliter per hour.During the same period of time, his estimated totalglucose pool decreased from 41.5 to 8.5 gm. At the firsthour, his rate of hepatic glucose production was morethan 30 gm. per hour, which is in good agreement withthe rates observed in five ketotic diabetic patients by Bondyet al.92 By the second hour, the rate of hepatic glucose pro-duction had fallen to normal (9 to 15 gm. per hour) andremained within the normal range through the first fourhours of treatment. Although total glucose disposal duringthe first hour of treatment was 41-0 gm., we were unableto determine whether this disappearance was due to uptakeby peripheral tissues or to urinary excretion since thepatient did not urinate until the second hour. At thesecond hour, it was noted that urinary glucose excretionhad accounted for approximately 80 per cent of the disposalof glucose. The mean hourly contribution of urinary glucoseexcretion to the disposal of glucose during the first sixhours of treatment averaged 82.3 ± 2.1 per cent (mean± S.E.M.). The hourly glucose utilization by the peripheraltissues averaged 3.4 gm. per hour during this time period anddid not appear to be influenced by either insulin therapy orby rehydration. That the rate of peripheral glucose utiliza-tion was found to be roughly one third of that in normalfasted man may have been due to the preferential utiliza-tion of ketone bodies by the brain and other tissues.93 Thesedata suggest that insulin administration decreases the rate ofhepatic glucose production but has little or no effect uponperipheral glucose utilization in the ketoacidotic patient.The primary mechanism for the disposal of glucose underthese conditions appears to be via urinary glucose excretion.

Consequently, the fall in the blood glucose concentrationduring the treatment of ketoacidosis can serve as an indexof the adequacy of rehydration and the restoration of renalblood flow. A failure of the blood glucose to fall wouldimply either inadequate volume expansion or a renal func-tional disorder. Since betahydroxybutyrate is excreted inthe urine as if there were a tubular maximum for its

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TABLE 3The fate of glucose during the first four hours of treatment of a 19-year-old man with severe diabetic ketoacidosis

Time(hour of

treatment)

Plasmaglucose

(mg./dl.)

Glucosepool size

(gm-)

Hepaticglucose

synthesis(gm./hr.)

Peripheralglucose

utilization(gm./hr.)

Urinaryglucose

excretion(gm./hr.)

Per cent of total glucosedisappearance due to

urinary excretion

01234

567385309177101

41.532.225.814.98.5

—31.7

7.99.4

11.2

——

5.37.80

No urineNo urine

22.312.531.1

——

80.775.584.0

reabsorption, it is not surprising that the rate of fall of theplasma betahydroxybutyrate parallels the fall in blood glucoseduring the treatment of diabetic ketoacidosis (figure I).67'94

In contrast, the blood acetone and acetoacetate concentra'tions frequently rise after the initiation of therapy creatinga condition in which reactivity of the serum to the nitn>prusside reagent would be expected to increase (figure 1).

In view of the effectiveness of rehydration in loweringthe blood glucose concentration and the effect of such alowering upon the distribution of fluids between the variouscompartments, we now recommend the early administrationof large volumes of isotonic saline. The scheme recentlyproposed by Jackson and Vinik in which two liters offluid are given within the first hour of therapy appearsto us to be somewhat excessive, and we have found that aninitial rate of one liter per hour of isotonic saline is ade-quate for most adults in ketoacidosis.95 Once a briskurine output is established (consistent with the existinghyperglycemia), we decrease the rate of fluid administrationto 500 ml. per hour. When the blood glucose falls below250 mg. per deciliter, we change to the infusion of 5 per centdextrose in 0.45 per cent saline at the rate of approxi-mately 250 ml. per hour. Obviously, these rates of fluidadministration are suggested for adults with previously normalrenal and myocardial function. In children, a reasonableinitial rate of fluid administration would be 20 ml. perkilogram per hour in the form of isotonic saline, changingto 10 ml. per kilogram per hour after the establishment of abrisk rate of urine flow. In the elderly and in patients withimpaired cardiac or renal function, the rate of fluid ad-ministration should be titrated against the central venouspressure.

As previously pointed out by Bradley, this form of fluidadministration, in which one attempts to restore the fluidlosses within a period of 12 to 24 hours, frequentlyleads to sodium retention and "insulin edema" for severaldays after the initiation of therapy.7 In the patient with nor-mal renal function, it is likely that this phenomenon is notdue to the administration of excessive amounts of sodiumchloride but is due instead to the antinaturetic effect of

insulin.7'96 Other mechanisms which may be involved inthis phenomenon include the antinaturesis induced byalkalinization as well as a delayed escape from elevatedserum aldosterone concentrations. We have found thatthis form of edema responds rapidly to the administra-tion of furosemide and will resolve spontaneously over aperiod of 24 to 48 hours if untreated.

Since the fluid losses incurred during the developmentof ketoacidosis are in the form of hypotonic fluids, nearlyall patients will have lost water in excess of the sodiumloss. Although one would anticipate hypematremia underthese circumstances, at the outset the serum sodium isartifactually decreased by the coexistent hyperglycemia.56

When the blood glucose is lowered by adequate rehydration,the preexisting hypematremia will be unmasked. Thus, thehypematremia and hyperchloremia which commonly developduring the treatment of diabetic ketoacidosis are largelydue to the antecedent hypotonic fluid losses rather than tothe overenthusiastic administration of isotonic saline. There-fore, we do not hesitate to initially administer isotonicfluids to maintain the intravascular volume, even at the riskof producing a transient hypematremia.

Potassium (20 mEq. per hour) should be administeredto all patients whose serum potassium is within or belowthe normal range at the outset. In those patients whoseserum potassium is elevated, we delay the administration ofpotassium until the urine output has been reestablished. Ifthe serum potassium concentrations are monitored at two-hour intervals, hypokalemia can be readily avoided. Oralpotassium supplements should be provided for the week fol-lowing recovery from diabetic ketoacidosis to permit thegradual restoration of the total potassium deficit.

As discussed previously, bicarbonate administration by al-tering the oxyhemoglobin dissociation curve may producetissue hypoxia and place undue stress upon the cardio-vascular system. Furthermore, if not accompanied by theadministration of potassium, rapid alkalinization can pre-cipitate severe hypokalemia, and the excessive administra-tion of bicarbonate may lead to the complications asso-ciated with postcorrection alkalosis.97 It is interesting that

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mortality figures as low as 1.5 per cent were observed inthe prebicarbonate era,98 and that more recent studies havesuggested that bicarbonate administration does not have anyeffect upon the recovery from diabetic ketoacidosis.99'100

Therefore, one could seriously question whether bicarbonateshould be used at all in the treatment of diabetic keto-acidosis.101 If it does little good and may precipitateshock and tissue hypoxia, we would suggest that the use ofthis compound in the treatment of diabetic ketoacidosisshould be as limited as possible.

Numerous authors have recommended the use of phosphatein the treatment of diabetic ketoacidosis. 53-95»102 It has beenknown for 30 years that the patient in diabetic ketoacidosisis phosphate depleted and that the serum phosphate con-centrations drop to abnormally low levels as a result oftreatment.103 More recently, a very close relationshipbetween the serum phosphate concentration and the restora-tion of erythrocyte 2,3-DPG towards normal has been ob-served in patients recovering from diabetic ketoacidosis.53

Ditzl has recommended that phosphate be administeredduring the early phases of therapy to hasten the recoveryof erythrocyte 2,3-DPG and to shorten the period of timeduring which the patient's tissues are exposed to hypoxia.Since it appears that the recovery of erythrocyte 2,3-DPGconcentrations occurs over a prolonged period of time, whatother therapeutic measures do we have to bridge this timegap? First, it makes sense to administer oxygen by mask orby nasal prongs to all patients during the treatment ofdiabetic ketoacidosis and for several days thereafter in olderpatients. Second, in a patient who is cyanotic or hypo-tensive, the administration of fresh whole blood (ifpossible obtained from a cigarette smoker with a high erythro-cyte 2,3-DPG concentration) might be of great value.Hopefully, within the next several years, controlled trials ofthe optimal form and rate of phosphate administration willbe carried out. In the interim, we recommend thatoxygen be administered and that the initial 100 mEq. ofpotassium in the intravenous fluids should be in the form ofbuffered potassium phosphate.

Other Therapeutic MeasuresIt almost goes without saying that any medical or surgicaldisease associated with or contributing to diabetic keto-acidosis must be promptly diagnosed and treated. In patientswith acute abdominal pain in association with ketoacidosis,it is our current practice to vigorously treat the keto-acidosis for three to four hours. If the pain and signs ofperitoneal irritation persist beyond that time, a laparotomyis performed in order to avoid the loss of a patient whoseketoacidosis was precipitated by an intraabdominal catas-trophe. We routinely aspirate the gastric contents of allsemicomatose and comatose patients to decrease the risk ofaspiration. Although we prefer to avoid catheterizationof the urinary bladder whenever possible, those patients

who are not capable of having urine samples collectedby other means are catheterized in order to maintainaccurate estimates of urinary output. The level of conscious-ness is assessed and the fundi are examined at hourly Iintervals to determine whether cerebral edema might be jdeveloping in patients under the age of 45 years. In the \event of a decreasing level of consciousness or thedevelopment of erythema or edema of the optic nerve head,a lumbar puncture is performed to determine the cere-brospinal fluid pressure. If the pressure is found to beabnormally elevated, the plasma osmolality can be in-creased by the administration of glucose or mannitol,steroids can be administered, and the neurosurgeonsshould be promptly consulted to determine the need fordecompression procedures.

Another aspect of therapy which has not been studied isthe effect of anticoagulants and inhibitors of plateletfunction on the mortality associated with diabetic keto- iacidosis. Our consideration of the factors which may lead Ito vascular thromboses in the treated ketoacidotic patient \would suggest that such therapeutic interventions mayhave a place in the treatment of this disorder. However,until the effectiveness of such therapeutic modalities in the j

prevention of delayed thromboses has been evaluated inlarge-scale trials, it is not possible to recommend their use.

CONCLUSION

Diabetic ketoacidosis continues to be a life-threateningcomplication of diabetes mellitus. The major causes of deathassociated with this condition are infection, vascular throm-boses, and shock. Hypoglycemia and hypokalemia arerarely seen with proper patient management. Many infec-tions can be successfully treated if they are rapidlyrecognized and if appropriate antibiotics are administered.Mechanisms that might play a role in the developmentof vascular thromboses and shock during the treatment ofdiabetic ketoacidosis have been discussed. It is suggestedthat the rapid expansion of the intravascular volume withisotonic saline, the avoidance of bicarbonate therapy, andthe administration of oxygen and phosphate, as well aswhole blood (in appropriate circumstances), might decreasethe frequency of these complications. Finally, the futurepossibility of the value of anticoagulation and/or inhibitionof platelet function as adjunctive measures in the treatmentof diabetic ketoacidosis is considered. We conclude thatwith appropriate therapy, it is now possible to drasticallyreduce the mortality associated with the treatment of diabeticketoacidosis.

ACKNOWLEDGMENTS: This work was aided by the MedicalResearch Service of the Veterans Administration, grantsfrom the Diabetes Trust Fund, the Juvenile Diabetes Founda-

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tion, and grants AM21065 and RR32 from the NationalInstitutes of Health.

From the Department of Medicine, Division of Endocrinologyand Metabolism, the Diabetes Research and Training Center,University of Alabama School of Medicine, and MetabolicResearch, Veterans Administration Hospital, Birmingham,Alabama.

Address reprint requests to R. S. Clements, Jr., VeteransAdministration Hospital, 700 South 19th Street, Birmingham,Alabama 35233 .

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Commission on Diabetes to the Congress of the United States,Volume III, part 2, pp. 88 -97 , 1976.

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7 Bradley, R. F.: Diabetic ketoacidosis and coma. In Joslin'sDiabetes Mellitus, 11th edit. Marble, A. , White, P., Bradley, R. F.,and Krall, L. P., Editors. Philadelphia, Lea &. Febiger, 1971,pp. 361-416.

8 McGarry, J. D., and Foster, D. W.: Ketogenesis and itsregulation. Am. J. Med. 61: 9 - 1 3 , 1976.

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24Kiraly, J. F., Becker, C. E., and Williams, H. E.: Diabeticketoacidosis: a review of cases at a university medical center.Calif. Med. 112: 1-9, 1970.

25 Beigelman, P. M.: Severe diabetic ketoacidosis (diabetic"coma"): 482 episodes in 257 patients; experience of threeyears. Diabetes 20: 490-500, 1971.

26 Alber t i , K. G . M. M . , Hockaday , T . D. R. , and Turne r ,R. C : Small doses of intramuscular insulin in the treatment ofdiabetic coma. Lancet 2: 515-22 , 1973.

27 Soler, N . C , Fitzgerald, M. G., Bennett, M. A. , and Malins,J. M.: Intensive care in the treatment of diabetic ketoacidosis.Lancet I: 951-54 , 1973.

28 Page, M. M., Alberti, K. G. M. M., Greenwood, R., Gumaa,K. A. , Hockaday, T. D. R., Lowy, C , Nabarro, J. D. N . , Pyke,D. A., S6nksen, P. H., Watkins, P. J., and West, T. E. T.: Treat-ment of diabetic coma with continuous low-dose infusion ofinsulin. Br. Med. J. 2: 687-90 , 1974.

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84 Quibrera , R., Nava , M . , DeLeon , E. D . , a n d Vidales, M . :T r e a t m e n t of diabet ic ketoacidosis, hyperosmolar coma and severediabetes with low I.V. i n t e rmi t t en t doses of insulin. Rev. Invest .Cl in . 28: 1 -6 , 1976.

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