Effects of sodium bicarbonate infusion on mortality in medical–surgical ICU patients with metabolic acidosis—A single-center propensity score matched analysis / Efectos de la infusión de bicarbonato de sodio sobre la mortalidad en pacientes de UCI médico-quirúrgica con acidosis metabólica: un análisis de puntuación de propensión en un solo Centro

Objective Metabolic acidosis is associated with high mortality. Despite theoretical benefits of sodium-bicarbonate (SB), current evidence remains controversial. We investigated SB-related effects on outcomes in ICU patients with metabolic acidosis. Design Retrospective analysis. Setting Academic medical center. Patients or participants 971 ICU patients with metabolic acidosis defined as arterial pH<7.3 and CO2<45mmHg treated between 2012 and 2016. A propensity score (PS) was estimated using logistic regression. Patients were matched in pairs using the PS. Interventions 441 patients were treated with SB 8.4% (SB-group) and n=530 patients were not (control group). Main variables of interest Primary outcome was all-cause mortality at ICU-discharge. Average Treatment Effect (ATE), Average Treatment effect in Treated (ATT), and estimated relative survival effects at 20 days were computed. Results In the full cohort, we observed considerable differences in pH, base excess, additional acidosis-related indices, and ICU mortality (controls 31% vs. SB-group 56%, p<.001) at baseline between the two groups. After PS-matching (n=174 in each group), no significant difference in ICU mortality was observed (controls 32% vs. SB-group 41%; p=.07). Odds ratios (OR) for ATE and ATT showed no association with ICU mortality (OR ATE: 1.08, 95%-CI 0.99–1.17; p=.08; OR ATT 1.09; 95%-CI 0.99–1.2; p=.09). Hazard ratios at 20-days (multivariable HR, matched sample n=348: 1.16, 95%-CI 0.86–1.56, p=.33) showed similar survival in the two study groups. Conclusions We did not observe effects of SB infusion on all-cause mortality in critically ill patients with metabolic acidosis (AU)

Objetivo La acidosis metabólica se asocia con una alta mortalidad. A pesar de los beneficios teóricos del bicarbonato de sodio (BS), la evidencia actual sigue siendo controvertida. Investigamos los efectos relacionados con el BS sobre los resultados en pacientes de la UCI con acidosis metabólica. Diseño Análisis retrospectivo. Ÿmbito Centro médico académico. Pacientes o participante Se incluyeron 971 pacientes de la Unidad de Cuidados Intensivos (UCI) con acidosis metabólica (pH < 7,3, CO2 < 45 mmHg) tratados entre 2012 y 2016. Se calculó una puntuación de propensión (PS) mediante regresión logística. Los pacientes se emparejaron utilizando el PS. Variables de interés principales Intervenciones; 441 pacientes fueron tratados con BS 8,4% (grupo BS) y n = 530 pacientes no (grupo control). Resultados El resultado primario fue la mortalidad por todas las causas al alta de la UCI. Se calcularon el efecto promedio del tratamiento (ATE), el efecto promedio del tratamiento en los tratados (ATT) y los efectos de supervivencia relativa estimados a los 20 días. En la cohorte completa se observaron diferencias considerables en el pH, el exceso de bases y la mortalidad en la UCI (control 31% vs. grupo BS 56%, p < 0,001) al inicio del estudio entre los grupos. Después del emparejamiento de PS (n = 174 en cada grupo), no se observaron diferencias significativas en la mortalidad en la UCI (control 32% vs. grupo BS 41%; p = 0,07). Los odds ratios (OR) para ATE y ATT no mostraron asociación con la mortalidad en la UCI (OR ATE: 1,08, IC 95%; 0,99-1,17; p = 0,08; OR ATT 1,09; IC 95%; 0,99-1,2; p = 0,09). Los cocientes de riesgo a los 20 días (HR multivariable, muestra emparejada n = 348: 1,16, IC 95%; 0,86-1,56, p = 0,33) mostraron una supervivencia comparable. Conclusiones No observamos efectos de la infusión de BS sobre la mortalidad por todas las causas en pacientes con acidosis metabólica (AU)

Characteristics of post-mortem beta-hydroxybutyrate-positivet cases - A retrospective study on age, sex and BMI in 1407 forensic autopsies.

BACKGROUND: Post-mortem biochemistry, including the analysis of beta-hydroxybutyrate (BHB), is increasingly employed in forensic medicine, especially in conditions such as diabetes and chronic alcoholism. However, not much is known about the associations between age, body mass index (BMI), and sex and BHB concentrations in ketoacidotic conditions. AIM: To retrospectively study the association between age, BMI and sex in several conditions, such as diabetic ketoacidosis (DKA), alcoholic ketoacidosis (AKA), and elevated post-mortem BHB concentrations. METHODS: 1407 forensic autopsy cases analysed for BHB were grouped by diagnosis: DKA, AKA, HHS [hyperosmolar hyperglycaemic state], acidosis NOS [not otherwise specified], or hypothermia. Age, sex, BMI and the concentrations of blood alcohol, vitreous glucose and blood BHB were recorded. RESULTS: Cases of AKA and DKA were most numerous (184 and 156, respectively). In DKA and in its male subgroup, cases with severe ketosis (BHB>1000 µg/g) were younger and had a lower BMI than those with moderate ketosis (BHB 250-1000 µg/g) and controls (P<0.001). In DKA and in its female subgroup, cases with moderate ketosis cases were older (P = 0.0218 and P = 0.0083) than controls. In AKA and in its male subgroup, cases with severe ketosis had a lower BMI than those with moderate ketosis (P = 0.0391 and P = 0.0469) and controls (P<0.001). Cases with moderate ketosis had a lower BMI than controls (P<0.001). CONCLUSIONS: BHB concentration is associated with BMI in DKA and AKA, and with both BMI and age in DKA. Constitutional factors should, therefore, be considered in potential AKA and DKA cases.

Postmortem diagnosis of ketoacidosis: Levels of beta-hydroxybutyrate, acetone and isopropanol in different causes of death.

Data from 496 autopsy cases with positive beta hydroxybutyrate (BHB), acetone or isopropanol in blood were investigated. The cases were divided into different groups according to cause of death. Cases with cause of death due to diabetic ketoacidosis (DKA, n=54) had the highest levels of BHB (median 1085mg/L) and acetone (median 330mg/L). Cases with cause of death due to alcoholic ketoacidosis (AKA, n=57) had high levels of BHB (median 500mg/L) and acetone (median 110mg/L). Cases with cause of death due to hypothermia (n=12) had similar BHB and acetone levels as the AKA group (median BHB 520mg/L and acetone 80mg/L). Cases with cause of death due to isopropanol intoxication (n=17) had high levels of isopropanol (median 430mg/L) and acetone (330mg/L), but undetected or low levels of BHB. Cases with cause of death due to other than the above mentioned (n=349) had median BHB levels of 100mg/L and median acetone levels of 20mg/L. BHB analysis is crucial for the diagnosis of postmortem ketoacidosis, since it is the main marker of ketoacidosis and helps distinguish between different causes of death. Acetone levels correlate with BHB levels in endogenous ketoacidosis, so acetone can be used as an initial screening marker to identify cases where BHB analysis should be performed, but positive acetone threshold should be maximum 20mg/L. Positive BHB is proof of endogenous ketoacidosis, whereas negative BHB indicates isopropanol intoxication or postmortem acetone/isopropanol formation by microorganisms in cases of decomposition. There is no correlation between BHB and the postmortem interval, and no sign of postmortem formation, so BHB analysis is useful even in cases of severe decomposition.

The logistic organ dysfunction system score predicts the prognosis of patients with alcoholic ketoacidosis.

Alcoholic ketoacidosis (AKA) is occasionally associated with multiple complications leading to death. However, no study has yet evaluated prognostic factors in patients with AKA. It is known that the logistic organ dysfunction system (LODS) score is an objective and useful index to predict the prognosis. We used LODS score to predict prognosis of AKA. We retrospectively reviewed the medical records of 46 patients who were diagnosed as AKA in our hospital. The mean LODS score was 6.3. The probability of mortality based on the LODS score was 36.6%, and 16 patients (34.5%) did, in fact, die. The total LODS score and lactate dehydrogenase (LDH) were significantly higher in the non-survival group. Prothrombin activity, serum platelet number, and the serum albumin levels were significantly higher in the survival group. We found significant correlations between the LODS score and arterial pH, the albumin level, and the LDH concentration. Multivariate analysis showed that the serum albumin and LDH levels were independently associated with survival in AKA patients. AKA patients suffered high-level mortality and the LODS score was an accurate predictor of prognosis. Clinicians may use the LODS score to this end.

[Alcoholic ketoacidosis ­ a review]. / Alkoholketoacidos är en väl dokumenterad men tämligen okänd diagnos - Möjlig orsak till dödsfall bland personer med alkoholproblem.

Alcoholic ketoacidosis - a review A chronic alcoholic with severe metabolic acidosis presents a difficult diagnostic problem in the emergency room. Over and above methanol- and ethylene glycol intoxication, alcoholic ketoacidosis is a common but less recognized etiology. The disorder occurs in alcoholics who have had a recent binge drinking followed by the abrupt cessation of alcohol consumption because of abdominal pain and vomiting, with resulting dehydration, starvation, and then a ß-hydroxybutyrate dominated ketoacidosis. Laboratory results may be misleading as the common urine-ketone tests may be negative or only weakly positive, since they only respond to acetoacetate. The short-term prognosis is good if treatment including replacement of fluid, electrolytes, glucose and thiamine is provided. However, recent studies have indicated that alcoholic ketoacidosis may be a significant cause of mortality in patients with alcohol dependence.

The cost of a case of subclinical ketosis in Canadian dairy herds.

The objective of this study was to develop a model to estimate the cost of a case of subclinical ketosis (SCK) in Canadian dairy herds. Costs were derived from the default inputs, and included increased clinical disease incidence attributable to SCK, $76; longer time to pregnancy, $57; culling and death in early lactation attributable to SCK, $26; milk production loss, $44. Given these figures, the cost of 1 case of SCK was estimated to be $203. Sensitivity analysis showed that the estimated cost of a case of SCK was most sensitive to the herd-level incidence of SCK and the cost of 1 day open. In conclusion, SCK negatively impacts dairy herds and losses are dependent on the herd-level incidence and factors included in the calculation.

Coût d'un cas d'acétonémie subclinique dans les troupeaux laitiers canadiens. L'objectif de cette étude consistait à développer un modèle pour estimer le coût d'un cas d'acétonémie subclinique (ASC) dans les troupeaux laitiers canadiens. Les coûts ont été dérivés des valeurs par défaut et comprenaient l'incidence accrue de maladie clinique attribuable à l'ASC, 76 $; un délai plus long avant la gestation, 57 $; la réforme et la mort au début de la lactation attribuable à l'ASC, 26 $; la perte de production laitière, 44 $. Compte tenu de ces chiffres, le coût de 1 cas d'ASC a été estimé à 203 $. Une analyse de sensibilité a montré que le coût estimé d'un cas d'ASC était le plus sensible à l'incidence de l'ASC au niveau du troupeau et au coût d'une journée ouvrable. En conclusion, l'ASC a un impact négatif sur les troupeaux laitiers et les pertes dépendent de l'incidence au niveau du troupeau et des facteurs inclus dans le calcul.(Traduit par Isabelle Vallières).

Hiperglucemia, cetoacidosis y lesión de Armanni-Ebstein: un caso ilustrativo / Hyperglycemia, ketoacidosis and Armanni-Ebstein lesion: an illustrative case

La cetoacidosis es una alteración metabólica que puede conducir a la muerte de forma rápida e inesperada y, por tanto, ser objeto de una autopsia judicial. Histológicamente se caracteriza por el hallazgo de vacuolas subnucleares en los túbulos proximales renales, la denominada lesión de Armanni-Ebstein (AE). Aunque suele ser de etiología diabética también puede tener otro origen, fundamentalmente alcohólico. Presentamos el caso de una mujer de 45 años con una historia de abuso de alcohol, se encuentra fallecida en su domicilio. Se observó hialinosis arteriolar, lesión AE en riñones y esteatosis en hígado; el estudio químico-toxicológico demostró cuerpos cetónicos en sangre y el análisis bioquímico del humor vítreo niveles de glucosa elevados. Se discute el origen más probable de cetoacidosis y la necesidad de un abordaje multidisciplinar en la investigación de las muertes súbitas inesperadas (AU)

The ketoacidosis is a metabolic disorder that may lead to unexpected sudden death and therefore be issued for a forensic autopsy. Its histopathology is characterized by subnuclear vacuoles in the renal proximal tubules, namely the Armanni-Ebstein (AE) lesion. It is usually caused by diabetes, although other origins are possible, mainly alcoholic abuse. We hereby show the case of a 45-year-old woman with a history of alcohol consumption found dead at her home. An arteriolar hyalinosis, AE lesion in kidneys and steatosis in the liver were found; results revealed ketonic bodies in blood and a high glucose value in vitreous humour. The most probable cause of ketoacidosis is discussed and also the need for a multidisciplinary approach in unexpected sudden deaths investigations (AU)

The postmortem diagnosis of alcoholic ketoacidosis.

AIMS: The aim of this article is to review the forensic literature covering the postmortem investigations that are associated with alcoholic ketoacidosis fatalities and report the results of our own analyses. METHODS: Eight cases of suspected alcoholic ketoacidosis that had undergone medico-legal investigations in our facility from 2011 to 2013 were retrospectively selected. A series of laboratory parameters were measured in whole femoral blood, postmortem serum from femoral blood, urine and vitreous humor in order to obtain a more general overview on the biochemical and metabolic changes that occur during alcoholic ketoacidosis. Most of the tested parameters were chosen among those that had been described in clinical and forensic literature associated with alcoholic ketoacidosis and its complications. RESULTS: Ketone bodies and carbohydrate-deficient transferrin levels were increased in all cases. Biochemical markers of generalized inflammation, volume depletion and undernourishment showed higher levels. Adaptive endocrine reactions involving insulin, glucagon, cortisol and triiodothyronine were also observed. CONCLUSIONS: Metabolic and biochemical disturbances characterizing alcoholic ketoacidosis can be reliably identified in the postmortem setting. The correlation of medical history, autopsy findings and biochemical results proves therefore decisive in identifying pre-existing disorders, excluding alternative causes of death and diagnosing alcoholic ketoacidosis as the cause of death.

[Postmortem differential diagnostics of diabetic and alcoholic ketoacidosis].

It was shown that ketoacidosis may be an immediate cause of death in subjects suffering chronic alcoholic intoxication. The authors present a list of biochemical studies and parameters that can be used for differential diagnosis between diabetic and alcoholic ketoacidosis.

Lethal hypoglycemic ketosis and glyceroluria in mice lacking both the mitochondrial and the cytosolic glycerol phosphate dehydrogenases.

The activities of either the mitochondrial or cytosolic glycerol phosphate dehydrogenase (mGPD, cGPD) plus that of glycerol kinase are required for the use of glycerol in aerobic metabolism and gluconeogenesis. A knockout mouse lacking mGPD has reduced body weight and fertility but shows remarkably normal liver and muscle metabolite levels. The BALB/cHeA mouse strain, which lacks cGPD, breeds well and is phenotypically normal, although it demonstrates metabolite abnormalities in certain tissues. Crosses were made between these two strains, and mice were generated that lacked both dehydrogenases. These mice, although active and nursing well for several days, failed to grow, and usually died within the first week. Liver glycerol phosphate levels were elevated 30-fold, whereas liver ATP, ADP, and AMP levels were reduced by 30-40%. Plasma glycerol was elevated 30- to 50-fold to 30-50 mm, and urine glycerol exceeded 0.45 m (4% w/v). GPD-deficient mice were hypoglycemic, had a 50% increase in plasma free fatty acids, and developed ketonuria within the first day of life. Uncoupling protein-1 mRNA in brown adipose tissue was reduced 60%. These mice share some features of both glycerol kinase deficiency and hereditary fructose intolerance, suggesting the phenotype may be due to the combined effects of the loss of a gluconeogenic substrate, the osmotic effects of glycerol, and the metabolic effects of the accumulation of a phosphorylated metabolite.

Base deficit does not predict mortality when secondary to hyperchloremic acidosis.

Base deficit has been established as a predictor of mortality and endpoint of resuscitation. We hypothesized that in a significant subset of surgical intensive care patients, base deficit is secondary to hyperchloremic acidosis, and that these patients experience lower mortality than those patients whose base deficits are secondary to other causes. Seventy-five consecutive surgical intensive care patients with base deficits greater than 2.0 were prospectively studied. The etiology of the patients' base deficits was determined by admission laboratory data. Patients were divided into those with hyperchloremic acidosis, and those with acidosis from other causes. Mortality within these groups was compared by Fisher's exact test. Thirty-seven patients (49.3%) had hyperchloremic acidosis. Thirty-three patients (46.7%) had lactic acidosis. Three patients (4%) had base deficits secondary to ketosis, and two patients (2.6%) had base deficits secondary to uremia. There were no significant differences in age, APACHE II scores, or volumes of resuscitation between the hyperchloremic group and the remaining patients. There were four deaths (10.8%) in the hyperchloremic group and thirteen deaths (34.2%) in the remaining patients (P = 0.03). Hyperchloremic acidosis resulted from resuscitation with lactated Ringer's solution in 18 (48.6%) of the hyperchloremic patients. Hyperchloremic acidosis is a common etiology of base deficit in the surgical intensive care unit. It is associated with lower mortality than base deficit secondary to other causes. Moreover, it is frequently induced following resuscitation with lactated Ringer's solution. Failure to properly diagnose this subset of acidotic patients may result in inappropriate clinical interventions due to the erroneous presumption of ongoing tissue hypoxia.

Alcoholic ketoacidosis at autopsy.

Total ketone bodies (acetone, acetoacetate, and beta-hydroxybutyrate) were measured in 105 medicolegal autopsies (71 non-alcoholics, 22 chronic alcoholics, and 12 diabetics) using a coupled enzymatic head-space gas chromatographic method. Samples included vitreous humour, pericardial fluid, and blood from the femoral vein, inferior vena cava (IVC), superior vena cava (SVC), and aorta. Vitreous ketone levels showed good correlation with blood and pericardial fluid levels, suggesting that vitreous could be used as an alternative autopsy specimen for this analysis. This opens up the possibility of using simpler clinical laboratory methodologies which cannot be applied to autopsy blood due to hemolysis. In 71 non-alcoholics (age 18 to 96, median 67) total ketones (mM/L) were: vitreous 0.19 to 3.35, median 0.49; pericardial fluid 0.02 to 1.54, median 0.35; femoral blood 0.23 to 8.08, median 1.00; aortic blood 0.25 to 9.96, median 0.90; IVC blood 0.30 to 6.49, median 1.27; SVC blood 0.32 to 6.00, median 1.07. Eleven outliers (> 2.5 mM/L in femoral blood) mostly had prolonged illness prior to death. The 22 alcoholics (age 36 to 83, median 62) included four extreme outliers with femoral blood total ketone levels of 129.9 (also diabetic), 39.4 (no anatomical cause of death), 38.5 (suicidal hanging), and 18.6 (hypothermia), suggesting that while alcoholic ketoacidosis may be a previously overlooked potential cause of death, interpretation must be guarded and made within the total case context. The other 18 alcoholics had ketone levels not statistically different from non-alcoholics, suggesting that ketoacidosis is a significant factor in at most a small minority of alcoholic deaths. Three of 12 diabetics had extreme elevations of femoral blood ketone bodies: 87.5, 20.4, and 17.4 mM/L. Measurement of ketone bodies in vitreous humour or pericardial fluid using clinical laboratory methodologies is recommended in unexplained deaths in chronic alcoholics as well as diabetics.

Ketoacidosis and lactic acidosis--frequent causes of death in chronic alcoholics?

In clinical medicine, severe keto- or lactic acidosis associated with vomiting, nausea, abdominal pain, tachycardia or pathological respiration, has been described in chronic alcoholics. This study reports on fatalities of chronic alcoholics where the cause of death could not be determined by thorough autopsy, histology and toxicology including determination of alcohol concentration. In a first series, acetone was determined in the blood of such chronic alcoholics (n = 24), diabetics with metabolic decompensation (n = 7), cases of hypothermia (n = 7) and controls (n = 218). Among the 24 chronic alcoholics where the cause of death was unknown, 9 cases showed very high levels of acetone (74-400 mg/l). These comprised 6 cases without additional findings and 3 cases where a second patho-mechanism such as intoxication possibly contributed to the cause of death. In a second series, the sum values according to Traub (lactate/glucose) were determined in cerebrospinal liquor of chronic alcoholics with undetermined cause of death (n = 45), diabetics (n = 6) and controls (n = 39). Among the 45 alcoholics, 17 cases showed very high sum values (294-594 mg/dl) including 8 cases where non-lethal intoxications may have contributed to the final outcome. Other causes of a ketoacidosis or lactic acidosis (e.g. diabetes) were excluded in both groups of alcoholics. Consequently, ketoacidosis and lactic acidosis can be the cause of death of chronic alcoholics in a considerable number of cases where no pathomorphological or toxicological changes are present. A scheme for medical and laboratory examination is described.

Alcoholic ketoacidosis as a cause of death in forensic cases.

Forensic pathologists are familiar with alcohol abusers, who are found dead and in whom the cause of death cannot be ascertained. In order to examine the possible role of ketoacidosis for the cause of death in this group of alcohol abusers, the concentrations of ketone bodies (acetone, acetoacetate, D-beta-hydroxybutyrate) were determined in post mortem blood specimens. Determination of the ketone body concentrations were made by a coupled enzymatic head-space gas chromatographic method. The material consisted of blood specimens from 131 deceased persons and was divided into three groups: Group 1: controls, 79 cases of non alcohol abusers; group 2: 35 cases of alcohol abusers with known causes of death and group 3: 17 cases of alcohol abusers without ascertainable cause of death. The geometric means for the sum of the ketone body concentrations in blood were: controls, 109 mumol/l; alcohol abusers with known causes of death, 152 mumol/l; and alcohol abusers without known cause of death, 590 mumol/l. The limit value between the controls and the group of alcoholics with unascertainable cause of death was by logistic regression found to be 531 mumol/l (343-1224 mumol/l). The term 'ketoalcoholic death' is, therefore, suggested, when the measured post mortem blood ketone body concentration in an alcoholic with otherwise unknown cause of death exceeds 531 mumol/l.

A review of deaths due to suspected lactic acidosis at a large metropolitan hospital.

A review of 2,647 consecutive deaths over a 19-month period at a large metropolitan hospital revealed 27 cases (1%) to be coded as metabolic acidosis. In ten of these deaths, a presumptive diagnosis of lactic acidosis could be made. Eight of the ten were diabetic, and all eight were treated with phenformin at the time of their last admission. Although phenformin could not be incriminated as the sole cause of lactic acidosis in these cases, a contributory role of the drug seems probable. The indiscriminate use of phenformin in diabetic patients should be discouraged and the contraindications to the use of phenformin should be stressed.