Mild Lactic Acidosis Research Articles

Thiamine-responsive pyruvate dehydrogenase complex deficiency presenting as recurrent muscle weakness: Identification of a novel mutation (p.T111I) in the PDHA1 gene.

Thiamine-responsive pyruvate dehydrogenase complex deficiency presenting as recurrent muscle weakness: Identification of a novel mutation (p.T111I) in the PDHA1 gene.

LBODP019 Vitamin D Levels In A Population With Type 2 Diabetes

Abstract Background Little is known about the impact of over-the-counter ketone supplementation, used by patients to promote weight loss, on ketosis and serum ketone values. Recent literature suggests that acute ingestion of exogenous ketones leads to increased blood beta-hydroxybutyrate and decreased blood glucose1. Clinical Case A 61-year-old man with a history of type 2 diabetes mellitus, atrial fibrillation, hypertension, and hyperlipidemia presented as a transfer to the neurocritical care ICU from an outside hospital for subarachnoid hemorrhage secondary to intracranial saccular aneurysm. His admission hemoglobin A1c was 9.9% (ref 4.4-5.6), blood glucose was 205 mg/dL (ref 70-99), beta-hydroxybutyrate was markedly elevated at 26.2 mg/dL (ref 0-3), and urinalysis showed 80mg/dL ketones (ref 0). Serum toxicology screen was notable for detectable acetone 8mg/dL (ref: none detected). His lactate was 2 mmol/L (ref 0.5-1.9), Cr 0.99mg/dL (0.67-1.17), and HCO3 22 mmol/L (ref 22-27). Arterial blood gas showed pH of 7.37 (ref 7.38-7.47), and an anion gap metabolic acidosis (AGMA) of 15 mmol/L (ref <12). Given the patient's profound ketosis, hyperglycemia, and mild AGMA, the patient was started on an insulin drip for presumed diabetic ketoacidosis (DKA). After 4 hours, the patient's anion gap had decreased to 12mmcol/L. The following day, he was transitioned to basal/bolus insulin, and underwent embolization of his cerebral aneurysm. After further recovery, Endocrinology was consulted for insulin recommendations. The patient denied any prior history of DKA or use of any SGLT2-inhibitors, and denied decreased oral intake or vomiting prior to admission. He did report taking ketone supplements, "Keto Strong: Ketogenic Weight Management – Advanced Formulation," two tabs (700mg "proprietary keto blend") BID for 2-3 years with ingredients listed as: sodium beta-hydroxybutyrate, calcium beta-hydroxybutyrate, magnesium beta-hydroxybutyrate, medium chain triglyceride oil, L-arginine, alpha-ketoglutaric acid, and 7-keto-dehydroepiandrosterone. Given a lack of acidosis, mild hyperglycemia, and mild lactic acidosis without risk factors for euglycemic DKA, it was suspected his profound ketosis out of proportion to clinical picture was secondary to ketone supplementation with a misdiagnosis of DKA. Conclusion This is one of the first cases to report profound ketosis in a hospitalized patient likely secondary to exogenous ketone supplementation. Ketosis secondary to nutritional supplementation should be considered once more common etiologies are ruled out. Additional research is needed to determine the role of exogenous ketone use on metabolism and glycemic control.

LBODP035 When Is Ketosis Just Ketosis?

Abstract Background Little is known about the impact of over-the-counter ketone supplementation, used by patients to promote weight loss, on ketosis and serum ketone values. Recent literature suggests that acute ingestion of exogenous ketones leads to increased blood beta-hydroxybutyrate and decreased blood glucose1. Clinical Case A 61-year-old man with a history of type 2 diabetes mellitus, atrial fibrillation, hypertension, and hyperlipidemia presented as a transfer to the neurocritical care ICU from an outside hospital for subarachnoid hemorrhage secondary to intracranial saccular aneurysm. His admission hemoglobin A1c was 9.9% (ref 4.4-5.6), blood glucose was 205 mg/dL (ref 70-99), beta-hydroxybutyrate was markedly elevated at 26.2 mg/dL (ref 0-3), and urinalysis showed 80mg/dL ketones (ref 0). Serum toxicology screen was notable for detectable acetone 8mg/dL (ref: none detected). His lactate was 2 mmol/L (ref 0.5-1.9), Cr 0.99mg/dL (0.67-1.17), and HCO3 22 mmol/L (ref 22-27). Arterial blood gas showed pH of 7.37 (ref 7.38-7.47), and an anion gap metabolic acidosis (AGMA) of 15 mmol/L (ref <12). Given the patient's profound ketosis, hyperglycemia, and mild AGMA, the patient was started on an insulin drip for presumed diabetic ketoacidosis (DKA). After 4 hours, the patient's anion gap had decreased to 12mmcol/L. The following day, he was transitioned to basal/bolus insulin, and underwent embolization of his cerebral aneurysm. After further recovery, Endocrinology was consulted for insulin recommendations. The patient denied any prior history of DKA or use of any SGLT2-inhibitors, and denied decreased oral intake or vomiting prior to admission. He did report taking ketone supplements, "Keto Strong: Ketogenic Weight Management – Advanced Formulation," two tabs (700mg "proprietary keto blend") BID for 2-3 years with ingredients listed as: sodium beta-hydroxybutyrate, calcium beta-hydroxybutyrate, magnesium beta-hydroxybutyrate, medium chain triglyceride oil, L-arginine, alpha-ketoglutaric acid, and 7-keto-dehydroepiandrosterone. Given a lack of acidosis, mild hyperglycemia, and mild lactic acidosis without risk factors for euglycemic DKA, it was suspected his profound ketosis out of proportion to clinical picture was secondary to ketone supplementation with a misdiagnosis of DKA. Conclusion This is one of the first cases to report profound ketosis in a hospitalized patient likely secondary to exogenous ketone supplementation. Ketosis secondary to nutritional supplementation should be considered once more common etiologies are ruled out. Additional research is needed to determine the role of exogenous ketone use on metabolism and glycemic control.

A CASE OF MIXED SEPTIC AND HEMORRHAGIC SHOCK DUE TO DISSEMINATED HISTOPLASMOSIS AND CRYPTOCOCCOSIS IN A PATIENT WITH HIV/AIDS

A CASE OF MIXED SEPTIC AND HEMORRHAGIC SHOCK DUE TO DISSEMINATED HISTOPLASMOSIS AND CRYPTOCOCCOSIS IN A PATIENT WITH HIV/AIDS

Pathogenic variants in MRPL44 cause infantile cardiomyopathy due to a mitochondrial translation defect

Cardiac dysfunction is a common phenotypic manifestation of primary mitochondrial disease with multiple nuclear and mitochondrial DNA pathogenic variants as a cause, including disorders of mitochondrial translation. To date, five patients have been described with pathogenic variants in MRPL44, encoding the ml44 protein which is part of the large subunit of the mitochondrial ribosome (mitoribosome). Three presented as infants with hypertrophic cardiomyopathy, mild lactic acidosis, and easy fatigue and muscle weakness, whereas two presented in adolescence with myopathy and neurological symptoms.We describe two infants who presented with cardiomyopathy from the neonatal period, failure to thrive, hypoglycemia and in one infant lactic acidosis. A decompensation of the cardiac function in the first year resulted in demise. Exome sequencing identified compound heterozygous variants in the MRPL44 gene including the known pathogenic variant c.467 T > G and two novel pathogenic variants. We document a combined respiratory chain enzyme deficiency with emphasis on complex I and IV, affecting heart muscle tissue more than skeletal muscle or fibroblasts. We show this to be caused by reduced mitochondrial DNA encoded protein synthesis affecting all subunits, and resulting in dysfunction of complex I and IV assembly. The degree of oxidative phosphorylation dysfunction correlated with the impairment of mitochondrial protein synthesis due to different pathogenic variants. These functional studies allow for improved understanding of the pathogenesis of MRPL44-associated mitochondrial disorder.

Always Read The Fine Print - Cyanide Toxicity From Ingestion Of Vitamin B17 Tablets: A Case Report

The use of vitamins and minerals as supplements is highly prevalent in most patient populations, owing to their purported long-term benefits and relative lack of harm on continued use. However, similarly marketed supplements may contain ingredients that can harm the user. Our case highlights a 45-year-old male who ingested several tablets of a supplement known as vitamin B17, Amygdalin, with subsequent fatigue, mild lactic acidosis, and worsening shortness of breath. He was treated as a case of cyanide toxicity based on clinical suspicion and improved subsequently. The case describes the potential harm from unregulated substances, particularly those purchased online. Vitamin B17, or Amygdalin, may be present in various anti-cancer supplementation and caution is advised in its use due to its association with cyanide poisoning.

Advances in Diagnosis of Mitochondrial Diseases: Case Report of an Infant with Pearson Syndrome

Pearson syndrome (PS) is a mitochondrial disorder that presents in early infancy as a multisystemic disease affecting the bone marrow and pancreas. It may present with anemia, diarrhea, exocrine pancreatic dysfunction, and failure to thrive.[1] Delay in diagnosis can lead to severe morbidity and mortality in infancy. We report the case of a 9-month-old presenting with failure to thrive, severe macrocytic anemia and pancytopenia initially thought to have gastroesophageal reflux and feeding intolerance. Severe macrocytic anemia and pancytopenia prompted an early bone marrow evaluation. Abnormal bone marrow findings including vacuolated marrow precursors and ringed sideroblasts along with persistent mild lactic acidosis led to a rapid and extensive genetics workup. Whole exome sequencing including mitochondrial genome sequencing detected a 2.3 kb heteroplasmic deletion in m.12113_14421 encompassing the MT-ND5 gene consistent with the diagnosis of Pearson Syndrome. This case report highlights the advances in molecular genetic testing to diagnose patients with complex medical histories along the spectrum of mitochondrial diseases and the importance of early diagnosis to start treatment.

Mitochondrial PCK2 Missense Variant in Shetland Sheepdogs with Paroxysmal Exercise-Induced Dyskinesia (PED).

Four female Shetland Sheepdogs with hypertonic paroxysmal dyskinesia, mainly triggered by exercise and stress, were investigated in a retrospective multi-center investigation aiming to characterize the clinical phenotype and its underlying molecular etiology. Three dogs were closely related and their pedigree suggested autosomal dominant inheritance. Laboratory diagnostic findings included mild lactic acidosis and lactaturia, mild intermittent serum creatine kinase (CK) elevation and hypoglycemia. Electrophysiological tests and magnetic resonance imaging of the brain were unremarkable. A muscle/nerve biopsy revealed a mild type II fiber predominant muscle atrophy. While treatment with phenobarbital, diazepam or levetiracetam did not alter the clinical course, treatment with a gluten-free, home-made fresh meat diet in three dogs or a tryptophan-rich, gluten-free, seafood-based diet, stress-reduction, and acetazolamide or zonisamide in the fourth dog correlated with a partial reduction in, or even a complete absence of, dystonic episodes. The genomes of two cases were sequenced and compared to 654 control genomes. The analysis revealed a case-specific missense variant, c.1658G>A or p.Arg553Gln, in the PCK2 gene encoding the mitochondrial phosphoenolpyruvate carboxykinase 2. Sanger sequencing confirmed that all four cases carried the mutant allele in a heterozygous state. The mutant allele was not found in 117 Shetland Sheepdog controls and more than 500 additionally genotyped dogs from various other breeds. The p.Arg553Gln substitution affects a highly conserved residue in close proximity to the GTP-binding site of PCK2. Taken together, we describe a new form of paroxysmal exercise-induced dyskinesia (PED) in dogs. The genetic findings suggest that PCK2:p.Arg553Gln should be further investigated as putative candidate causal variant.

Heart transplant complicated by metformin induced lactic acidosis

Introduction Mild lactic acidosis following heart transplant is a known laboratory finding that generally does not require treatment. However, we encountered a case in which a diabetic patient on metformin underwent a heart transplant and developed a profound rise in lactate which caused a severe anion gap metabolic acidosis and refractory vasoplegia. Methods Case Report. Results A 52 year old man with a past medical history of type 2 diabetes mellitus managed with metformin, chronic kidney disease, and coronary artery disease underwent an LVAD explant and a heart transplant utilizing bicaval anastomosis technique. Twenty minutes after separating from bypass, an arterial blood gas was notable for a lactate of 7.8 mmol/L. Over the next two hours, the patient developed vasoplegia and a severe anion gap metabolic acidosis with a lactate that peaked at 18.0 mmol/L. TEE and surgical visualization agreed that cardiac function was excellent and without evidence of tamponade. The patient's hyperdynamic cardiac function was confirmed by the cardiac output values nearing 14 L/m via Swan-Ganz thermodilution. The patient's preoperative medication history was once more analyzed and metformin induced lactic acidosis was added to our working differential diagnosis. A dialysis line was placed, and continuous veno-venous hemofiltration (CVVH) was initiated in the OR, followed by a downtrend of lactate and improvement in hemodynamics. CVVH was continued in the ICU resulting in resolution of lactemia. Discussion Metformin induced lactic acidosis is rare and a diagnosis of exclusion. We ruled out hypovolemia due to a CVP of 14-15 mmHg and ischemic bowel by benign abdominal exam and normal AST, ALT, amylase, and lipase. Sepsis was considered less likely due to lack of infectious source/fever and maintenance of scheduled antibiotic prophylaxis. We had established that the donor cardiac function was excellent. Due to the unpredictable nature of heart transplant, our patient received metformin within 48 hours of surgery. The patient's known chronic kidney disease, potentially exacerbated by cardiopulmonary bypass, likely contributed to metformin induced lactic acidosis.

1117-P: Metformin Increases Blood Lactic Acid in Elderly Diabetic Veterans with Stage 3 CKD

Aim: Recently, the FDA endorsed metformin (MET) use in type 2 diabetes (T2D) patients with stage 3 CKD (CKD3). However, MET safety in elderly T2D subjects with CKD3 is unknown. Methods: We studied lactic acid (LA) levels in ambulatory elderly male U.S. Veterans with stable nondiabetic CKD3 (eGFR 30-59ml/min/1.73m2) (Group 1) and diabetic CKD3 not on MET (Group 2) and on MET (Group 3) for at least 6 months. Hyperlactatemia was defined as LA >2mmol/L. Patients with history of HIV, advanced CHF, alcohol abuse, and liver cirrhosis were excluded. Clinical and biochemical characteristics were analyzed using ANOVA, χ2 test and Fisher’s exact tests. Results: Mean LA levels were similar at 1.3±0.3 and 1.3±0.4 mmol/L in Group 1 (N=24, age 74.9±6.4 years, BMI 29.5±4.0kg/m2) and Group 2 (N=28, age 74.4±6.2 years, BMI 32.5±5.8kg/m2), respectively; while, LA was significantly higher in Group 3 (N=40, age 71.7±5.0 years, BMI 33.9±7.5kg/m2) at 2.0±1.0mmol/L compared with Group 2 subjects (P<0.001). Only 1 patient in each Group 1 (4.2%) and Group 2 (3.6%) had hyperlactatemia, as compared with 17 pts in Group 3 (42.5%) (P<0.05). Mild lactic acidosis (LA 5.2mmol/L, bicarbonate 18meq/L, anion gap 16) resolving with MET discontinuation was diagnosed in one Group 3 subject. Average daily MET dose in Group 3 was 1325±581mg and glycemic control was equal in Groups 2 and 3 (HbA1c 7.5±1.3 vs. 7.6±1.3%). There was no difference in mean LA level or frequency of hyperlactatemia between Group 3 pts with CKD stage 3A (eGFR 45-59, MET 1394±619mg/day) and stage 3B (eGFR 30-44, MET 1000±0mg/day). No differences in age, BMI, weight, eGFR, and HbA1c were seen in Group 3 pts with and without hyperlactatemia except trend towards higher MET dose in the hyperlactatemia patients (1500±560 vs. 1196±574 mg/day, P=0.1). Conclusions: MET increases risk of hyperlactatemia in elderly men with T2D and CKD3 without clear predisposing factors while not offering explicit therapeutic advantage. We recommend using lower MET doses in elderly diabetic men with stage 3 CKD. Disclosure A.R. Gosmanov: None. E. Gosmanova: Advisory Panel; Self; Amgen Inc.

Lysine desuccinylase SIRT5 binds to cardiolipin and regulates the electron transport chain

SIRT5 is a lysine desuccinylase known to regulate mitochondrial fatty acid oxidation and the urea cycle. Here, SIRT5 was observed to bind to cardiolipin via an amphipathic helix on its N terminus. In vitro, succinyl-CoA was used to succinylate liver mitochondrial membrane proteins. SIRT5 largely reversed the succinyl-CoA-driven lysine succinylation. Quantitative mass spectrometry of SIRT5-treated membrane proteins pointed to the electron transport chain, particularly Complex I, as being highly targeted for desuccinylation by SIRT5. Correspondingly, SIRT5-/- HEK293 cells showed defects in both Complex I- and Complex II-driven respiration. In mouse liver, SIRT5 expression was observed to localize strictly to the periportal hepatocytes. However, homogenates prepared from whole SIRT5-/- liver did show reduced Complex II-driven respiration. The enzymatic activities of Complex II and ATP synthase were also significantly reduced. Three-dimensional modeling of Complex II suggested that several SIRT5-targeted lysine residues lie at the protein-lipid interface of succinate dehydrogenase subunit B. We postulate that succinylation at these sites may disrupt Complex II subunit-subunit interactions and electron transfer. Lastly, SIRT5-/- mice, like humans with Complex II deficiency, were found to have mild lactic acidosis. Our findings suggest that SIRT5 is targeted to protein complexes on the inner mitochondrial membrane via affinity for cardiolipin to promote respiratory chain function.

The Association Between Admission Magnesium Concentrations and Lactic Acidosis in Critical Illness.

Although magnesium plays an important role in aerobic metabolism and magnesium deficiency is a common phenomenon in critical illness, the association between magnesium deficiency and lactic acidosis in the intensive care unit (ICU) has not been defined. This was a retrospective, cross-sectional study conducted at a 77 ICU bed tertiary medical center. Data pertaining to the first unique admission of any ICU patient between 2001 and 2008 were extracted from the Multiparameter Intelligent Monitoring in Intensive Care database. Hypomagnesemia was defined as serum magnesium <1.6 mg/dL. Mild and severe lactic acidosis were defined as lactate concentrations of >2 and > 4 mmol/L, respectively. Multivariate modeling was used to explore the association between magnesium and lactate concentrations. Of 8922 critically ill patients, 22.6% were hypomagnesemic. Hypomagnesemia was associated with an increased adjusted risk of mild lactic acidosis (odds ratio [OR] 1.71, 95% confidence interval [95%CI] 1.51-1.94, P < .001) and severe lactic acidosis (OR 1.56, 95%CI 1.32-1.84, P < .001) than the reference quartile. The association between hypomagnesemia and mild lactic acidosis was stronger in those at risk of magnesium deficiency, including diabetics (OR 2.02, 95%CI 1.51-2.72, P < .001) and alcoholics (OR 1.92, 95%CI 1.16-3.19, P = .01). As an internal model control, hypokalemia was not associated with an increased risk of lactic acidosis. Magnesium deficiency is a common finding in patients admitted to the ICU and is associated with lactic acidosis. Our findings support the biologic role of magnesium in metabolism and raise the possibility that hypomagnesemia is a correctable risk factor for lactic acidosis in critical illness.

HIV and the Bone

At the end of 1999 my friend Marco Borderi came to me with a ‘‘hot’’ question: ‘‘I’m afraid that my HIV-positive patients can develop osteoporosis: how can we manage it?’’ I had been working on metabolic bone diseases since 1995, and I supposed I could treat his patients like all the others. We began to screen all HIV-positive subjects with dual X-ray absorptiometry (DXA), and we had the first surprise: A very high number of them had low bone mass, despite their relative young age. Moreover, males seemed to have a worse BMD than females. Some literature data were available involving mesenchymal stem cell infection, protease inhibitors, mild lactic acidosis and alterations in vitamin D metabolism and in bone turnover as possible etiological mechanisms of HIV-related metabolic bone disease. Finally, by those times none of us knew how to treat these patients. As survival of HIV-positive individuals was rapidly increasing, we were forced to go deeper in the comprehension of HIV-related osteoporosis, and we wrote our first paper reporting prevalence of osteopenia and osteoporosis. Soon after, we joined some other Italian groups facing this problem, and we began to collaborate with Dr. Guaraldi, a well-known opinion leader in the field of HIV infection, who rapidly became a very good friend of mine. With him we conducted a pilot multicenter randomized study testing alendronate efficacy in reducing bone turnover of HIVpositive patients. Dr. Gibellini joined us later bringing his basic knowledge for the study of cellular cross talking. Meanwhile, all over the world, literature was very rapidly growing, and in 2005, I received a surprising e-mail from Dr. Brown. In those days Todd was writing his fundamental meta-analysis on HIV-related osteoporosis, and he asked me for some of my unpublished data in order to include our paper in his work. Since then, a very long distance has been covered, but we still have a long way to go. This issue of Clinical Reviews in Bone and Mineral Metabolism aims to provide its readers a focus on different important aspects of HIV-related bone disease. To achieve this goal, we have called all the aforementioned friends together with Dr. Mallon, Dr. Ross and Dr. McComsey that are world-renowned researchers in this particular field. Drs. Gibellini, Borderi, Vanino, Clo, Morini, Calza, Re and Viale will summarize the molecular bases of osteoporosis in HIV, highlighting the role of the virus and of antiretroviral therapy. Drs. Harris and Brown will review the prevalence of osteopenia, osteoporosis and fractures, while Drs. Guaraldi, Santoro and Domingues da Silva will focus on the aging skeleton. Drs. Cotter and Mallon are going deeper inside the emerging field of the cross talk between bone and fat in HIV-infected patients. Finally, Drs. Ross and McComsey will review the role of vitamin D deficiency in the pathogenesis of osteoporosis and in the modulation of the immune system in HIV-related bone disease. On behalf of Dr. Angelo Licata, the Editor-in-Chief of CRBMM, and the authors of the reviews, I hope you will enjoy the articles complied within this special issue. I am also confident that they will provide useful information in the wide field of HIV-related osteoporosis and possibly will stimulate interest and research in the years ahead. F. Vescini (&) Endocrinology and Metabolism Unit, University-Hospital S. Maria della Misericordia, P.le S. Maria della Misericordia, 15, 33100 Udine, Italy e-mail: fvescini@alice.it

The cardiovascular, respiratory, and metabolic effects of a long duration electronic control device exposure in human volunteers

Electronic control devices (ECD) have become popular in law enforcement because they have filled a gap left by other law enforcement devices, tactics, or tools and have been shown to reduce officer and suspect injuries. Civilians are using the same technology for defensive purposes. TASER C2 is the latest generation civilian-marketed device from the manufacturer. Unlike the law enforcement devices, the device discharges for 30s continuously. This study is the first to look at the cardiovascular, respiratory, and metabolic effects of this device on human subjects. This was a prospective, observational study of human subjects involved in a training course. Subjects were exposed for 30s on the anterior thorax. Vital signs, ECG, troponin I, pH, lactate, and creatine kinase (CK) were measured before and immediately after the exposure. Troponin I, pH, lactate, and CK were measured again 24h after the exposure. Continuous spirometry was used to evaluate the respiratory effects. Echocardiography was also performed before, during, and immediately after the exposure to determine heart rate and rhythm. Eleven subjects completed the study. There were no clinically important electrocardiogram changes and no positive troponins. Spirometry showed an increase in minute ventilation during the exposure. There was no important change in CK at 24h. Lactate was slightly higher and pH was slightly lower after the exposure, but similar to the effects of physical exertion. Echocardiography was performed in 6 subjects. In half of these subjects, the rhythm was determined to be "sinus" and in the other half the rhythm was indeterminant. In our study, the civilian device caused a mild lactic acidosis. No other important physiologic effects were found.

MLASA syndrome: a case report.

Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) syndrome is a rare autosomal recessive disorder of oxidative phosphorylation and iron metabolism. The association between myopathy and sideroblastic anemia was initially reported in 1974. Here we report an 8.5 year old boy with normal cognitive function, suffering from chronic progressive weakness in his lower extremities, inability to walk and palor. Microcytic sideroblastic anemia, mild lactic acidosis and inflammatory myopathy (myositis) in muscle biopsy was detected and treated; the response to corticosteroid therapy and rehabilitation was excellent and the patient was ambulatory after four months.

Neonatal hemodynamic responses to extreme ranges of controlled graded hypoxia.

To determine the hemodynamic responses to a wide range of specific, controlled, graded levels of hypoxic hypoxia over 120 mins in a neonatal porcine model and to identify the PaO2 threshold for altered hemodynamic homeostasis. Prospective, experimental, animal study. University cardiovascular research laboratory. Three-day-old domestic swine. Anesthetized, intubated, and ventilated 3-day-old pigs (n = 88) were assigned to one of five predetermined graded PaO2 groups: Group I (normoxia, PaO2 = 80 torr [10.7 kPa]); group II (PaO2 = 60 torr [8.0 kPa]); group III (PaO2 = 40 torr [5.3 kPa]); group IV (PaO2 = 30 torr [4.0 kPa]); or group V (PaO2 = 20 torr [2.7 kPa]). Hemodynamic parameters including heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure (MAP), and pulse pressure were evaluated. Acid-base status (arterial pH and lactate) was monitored in each experimental group over the 120-min study period. Hemodynamic and acid-base parameters were unaltered in animals in groups I and II. In group III animals, blood pressure was maintained (partly by increased heart rate), and acid-base balance was unaltered. In contrast, group IV animals had a gradual and progressive decrease in systolic blood pressure, diastolic blood pressure, and MAP, and slightly decreased pulse pressure, despite sustained tachycardia. Group IV animals also developed mild lactic acidosis. Group V animals exhibited a biphasic hemodynamic response, while the heart rate response was characterized by tachycardia at the induction of hypoxia, which was reduced in magnitude by 120 mins. The biphasic hemodynamic response in this group of animals included an initial increase in systolic and pulse pressures, followed by a gradual and progressive decrease in systolic and diastolic blood pressures, MAP, and pulse pressure. In addition, group V animals also developed profound progressive lactic acidosis. In anesthetized neonatal pigs, tachycardia occurred in response to a PaO2 of 40 torr (5.3 kPa), and thus marked the threshold for altered hemodynamic homeostasis. Beyond this threshold, both the 30 torr (4.0 kPa) and 20 torr (2.7 kPa) groups had a PaO2- dependent "late" hypotension, while only the 20 torr (2.7 kPa) group had a significant biphasic hemodynamic response characterized by "early" hypertension. The "late" hypotension which occurred in these two profound hypoxia groups indicates an inability to adequately adjust hemodynamics during prolonged hypoxic hypoxia.

Primary treatment of propionic acidemia complicated by acute thiamine deficiency

Propionic acidemia is often manifested during the neonatal period with vomiting, failure to thrive, lethargy, and hyperammonemic coma when catabolism is prolonged. Mild lactic acidosis frequently accompanies metabolic decompensation. We present two patients with propionic acidemia whose initial manifestation was complicated by severe lactic acidosis caused by thiamine deficiency, which resulted from an inadequate supply of, and an increased need for, thiamine during metabolic stress. To prevent acute thiamine deficiency, we propose early vitamin supplementation during treatment of any severe metabolic decompensation accompanied by insufficient food intake. (J Pediatr 1996;129:758-60)

Cerebral oxygen and glucose metabolism and blood flow in mitochondrial encephalomyopathy: a PET study

Cerebral blood flow (CBF), oxygen metabolism (CMRO2), and glucose metabolism (CMRGlc) were measured using positron emission tomography in five patients diagnosed as having mitochondrial encephalomyopathy. The molar ratio between the oxygen and glucose consumptions was reduced diffusely, as CMRO2 was markedly decreased and CMRGlc was slightly reduced. The CBF showed less changes. The CBF increase on hypercapnia was smaller than normal, though this was not significant. CBF with hypocapnia demonstrated a significant reduction compared with the normal. These results suggest that oxidative metabolism is impaired and anaerobic glycolysis relatively stimulated, due to a primary defect of mitochondrial function, and that mild lactic acidosis occurs in brain tissue because of impaired utilisation of pyruvate in the TCA cycle. As these findings appear to indicate directly a characteristic of this disease, such measurements may be a useful tool for assessment of the pathophysiology and for diagnosis of mitochondrial encephalomyopathy.

Comparative lactic acidosis in fishes following pesticide stress

Lactic acid levels were estimated in blood, liver, muscle and heart-tissues of a water-breathing fish, Sarotherodon mossambicus and of an air-breathing fish, Channa striatus under control and 3 ppm sevin-exposed (for 24 h, 48 h, 72 h and 96 h) conditions. Based on the results obtained, the following points were concluded: (1) The water-breathing fish, S. mossambicus appeared to suffer severe lactic acidosis to a greater extent than that of the air-breathing fish, C. striatus during early periods (24 h) of sevin exposure. (2) Following prolonged exposure for 48 h and 72 h, S. mossambicus exhibited adaptive withdrawal of lactic acid from blood and muscle possibly into liver favouring the synthesis of glycogen (glycogenesis through Cori cycle) from lactic acid under sevin toxicity. (3) The reduction in lactic acid level in blood, liver and muscle of the air-breathing fish, C. striatus, under sevin exposure for 24 h and 48 h was suggestive of a possible oxidation of lactic acid (by rechannelling lactic acid into Krebs cycle via pyruvic acid) to meet the energy demand under sevin toxicity. (4) The onset of mild lactic acidosis in blood, muscle and liver during 72 h of sevin exposure of C. striatus suggested a possible inhibition of enzyme battery in the conversion of lactic acid into pyruvic acid.

Defects of the mitochondrial respiratory chain complexes in three pediatric cases with hypotonia and cardiac involvement

Three children displaying hypotonia, cardiac involvement and defects of the mitochondrial respiratory chain complexes are reported. The first case showed severe neonatal hypotonia, failure to thrive, hepatomegaly, dilation of the right cardiac cavities, profound lactic acidosis and amino aciduria. The boy died at the age of 7 weeks. In the second case hypotonia, severe cardiomyopathy, cyclic neutropenia, lactic acidosis and 3-methylglutaconic aciduria occurred. The boy died at the age of 27 months. The third case presented at the age of 16 months as an acute hypokinetic hypertrophic cardiomyopathy with transient hypotonia and mild lactic acidosis. Spontaneous clinical remission occurred. In all cases muscle biopsy was performed. Morphological studies failed to show ragged-red fibers but there was lipid storage myopathy and decreased cytochrome c oxidase activity. Biochemical studies confirmed the cytochrome c oxidase deficiency in muscle in all cases. It was associated with complex I III deficiency in case I and with severe deficits of all respiratory chain complexes in case 2. Post-mortem studies in case I indicated that complex IV was reduced in the liver but not in the heart and quantitative analysis of mtDNA revealed a depletion in muscle. Cases 1 and 2 shared some clinical features with fatal infantile myopathy associated with cytochrome c oxidase deficiency, while case 3 displayed a very unusual clinical presentation. The histochemical enzyme reaction of cytochrome c oxidase is useful for the diagnosis of mitochondrial myopathy because ragged-red fibers may be lacking. Finally, biochemical measurement of the different mitochondrial respiratory chain complexes is required because multiple defects are frequent and occasionally related to mtDNA depletion.