A Comparison of the Effects of Skeletal Trauma and Surgery on the Ketosis of Starvation in Man

Birkhahn, Ronald H.; Long, Calvin L.; Fitkin, David L.; Busnardo, Antonio C.; Geiger, John W.; Blakemore, William S.

doi:10.1097/00005373-198107000-00002

Cited by 59 publications

(13 citation statements)

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“…With late-PN, and thus with accepting an important macronutrient deficit during the first week in the PICU, plasma 3HB concentrations were found to rise up to the millimolar range. This high level of plasma 3HB in response to late-PN was striking given that earlier studies had suggested impaired ketogenesis during critical illness in adults [22][23][24][25]. Hyperinsulinemia and hyperglycemia are powerful suppressors of ketogenesis and hallmarks of critical illness [20,21].…”

Section: Discussionmentioning

confidence: 80%

“…In critical illness, however, although plasma glucagon, cortisol, and catecholamines are elevated, concomitant hyperinsulinemia and hyperglycemia may suppress ketogenesis [20,21]. In line with this, available data, though scarce, suggested suppressed ketogenesis during critical illness [22][23][24][25]. Withholding early-PN has shown to reduce the degree of hyperglycemia, to lower the insulin requirements to prevent hyperglycemia [4,5], and to lower the insulin/glucagon ratio [26].…”

Section: Introductionmentioning

confidence: 99%

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Effect of withholding early parenteral nutrition in PICU on ketogenesis as potential mediator of its outcome benefit

et al. 2020

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Background: In critically ill children, omitting early use of parenteral nutrition (late-PN versus early-PN) reduced infections, accelerated weaning from mechanical ventilation, and shortened PICU stay. We hypothesized that fasting-induced ketogenesis mediates these benefits. Methods: In a secondary analysis of the PEPaNIC RCT (N = 1440), the impact of late-PN versus early-PN on plasma 3-hydroxybutyrate (3HB), and on blood glucose, plasma insulin, and glucagon as key ketogenesis regulators, was determined for 96 matched patients staying ≥ 5 days in PICU, and the day of maximal 3HB-effect, if any, was identified. Subsequently, in the total study population, plasma 3HB and late-PN-affected ketogenesis regulators were measured on that average day of maximal 3HB effect. Multivariable Cox proportional hazard and logistic regression analyses were performed adjusting for randomization and baseline risk factors. Whether any potential mediator role for 3HB was direct or indirect was assessed by further adjusting for ketogenesis regulators. Results: In the matched cohort (n = 96), late-PN versus early-PN increased plasma 3HB throughout PICU days 1-5 (P < 0.0001), maximally on PICU day 2. Also, blood glucose (P < 0.001) and plasma insulin (P < 0.0001), but not glucagon, were affected. In the total cohort (n = 1142 with available plasma), late-PN increased plasma 3HB on PICU day 2 (day 1 for shorter stayers) from (median [IQR]) 0.04 [0.04-0.04] mmol/L to 0.75 [0.04-2.03] mmol/L (P < 0.0001). The 3HB effect of late-PN statistically explained its impact on weaning from mechanical ventilation (P = 0.0002) and on time to live PICU discharge (P = 0.004). Further adjustment for regulators of ketogenesis did not alter these findings. Conclusion: Withholding early-PN in critically ill children significantly increased plasma 3HB, a direct effect that statistically mediated an important part of its outcome benefit.

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Effect of withholding early parenteral nutrition in PICU on ketogenesis as potential mediator of its outcome benefit

et al. 2020

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“…Changes in non-esterified fatty acids and 3-hydroqbutyrate were variable and not significant, presumably because the effect of starvation in increasing their concentrations was counteracted by the effect of injury [17]. Creatinine concentrations were essentially unchanged throughout the study.…”

Section: Resultsmentioning

confidence: 88%

Plasma Leptin, Energy Intake and Hunger following Total Hip Replacement Surgery

Stratton¹,

Dewit²,

Crowe³

et al. 1997

Clinical Science

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1. This study aimed to investigate the possible role of leptin in post-traumatic anorexia by making pre- and post-operative (0-8 days) measurements of circulating leptin concentrations in six patients undergoing elective total hip replacement for osteoarthritis. 2. Mean daily hunger rating (four categories) and food intake (assessed by food record charts) were measured pre-operatively, as well as post-operatively for the first 5 days (days 0-5). Leptin concentrations, circulating metabolites [glucose, non-esterified fatty acids, glutamine and 3-hydroxybutyrate] and insulin and cortisol concentrations were measured pre-operatively (day 0) and post-operatively (days 1, 2, 3, 5 and 8). 3. Mean leptin concentrations were significantly increased only on day 1 (56% increase compared with pre-operative values, P < 0.009), whereas food intake (only 0.6 MJ on day 0) and hunger (5/6 patients 'not hungry' on day 0) only gradually improved over the next few days. (The energy intake over the first 5 days was 56% of the pre-operative value.) 4. Circulating insulin and cortisol concentrations were elevated on day 1 compared with pre-operative values on day 0 (P < 0.05). Of the measured metabolites implicated in the control of food intake, circulating non-esterified fatty acids and 3-hydroxybutyrate were not significantly altered in the post-operative period, but significant hyperglycaemia was noted on day 1 compared with day 0 pre-operatively (8.8 compared with 6.4 mmol/l glucose; P < 0.01). 5. It is concluded that circulating leptin is involved in the early (< 24 h) acute-phase response after moderately severe surgical trauma (characterized biochemically by a substantial acute-phase protein response, hypoalbuminaemia, hyperglycaemia and hypoglutaminaemia). Therefore, leptin may be implicated in post-traumatic anorexia, although other factors are likely to be involved, especially after the first 24 h when circulating leptin concentrations are no longer elevated.

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“…Critical illness in lean patients is characterized by impaired ketogenesis and reduced hepatic and muscular fatty acid metabolism [41][42][43]. Remarkably, overweight/ obese septic mice did not display such impairment but maintained the typical metabolic profile present with diet-induced obesity (enhanced lipolysis and elevated hepatic fatty acid metabolism) [16-20, 22, 23].…”

Section: Discussionmentioning

confidence: 99%

Adipose tissue protects against sepsis-induced muscle weakness in mice: from lipolysis to ketones

et al. 2019

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Background: ICU-acquired weakness is a debilitating consequence of prolonged critical illness that is associated with poor outcome. Recently, premorbid obesity has been shown to protect against such illness-induced muscle wasting and weakness. Here, we hypothesized that this protection was due to increased lipid and ketone availability. Methods: In a centrally catheterized, fluid-resuscitated, antibiotic-treated mouse model of prolonged sepsis, we compared markers of lipolysis and fatty acid oxidation in lean and obese septic mice (n = 117). Next, we compared markers of muscle wasting and weakness in septic obese wild-type and adipose tissue-specific ATGL knockout (AAKO) mice (n = 73), in lean septic mice receiving either intravenous infusion of lipids or standard parenteral nutrition (PN) (n = 70), and in lean septic mice receiving standard PN supplemented with either the ketone body 3hydroxybutyrate or isocaloric glucose (n = 49). Results: Obese septic mice had more pronounced lipolysis (p ≤ 0.05), peripheral fatty acid oxidation (p ≤ 0.05), and ketogenesis (p ≤ 0.05) than lean mice. Blocking lipolysis in obese septic mice caused severely reduced muscle mass (32% loss vs. 15% in wild-type, p < 0.001) and specific maximal muscle force (59% loss vs. 0% in wild-type; p < 0.001). In contrast, intravenous infusion of lipids in lean septic mice maintained specific maximal muscle force up to healthy control levels (p = 0.6), whereas this was reduced with 28% in septic mice receiving standard PN (p = 0.006). Muscle mass was evenly reduced with 29% in both lean septic groups (p < 0.001). Lipid administration enhanced fatty acid oxidation (p ≤ 0.05) and ketogenesis (p < 0.001), but caused unfavorable liver steatosis (p = 0.01) and a deranged lipid profile (p ≤ 0.01). Supplementation of standard PN with 3-hydroxybutyrate also attenuated specific maximal muscle force up to healthy control levels (p = 0.1), but loss of muscle mass could not be prevented (25% loss in both septic groups; p < 0.001). Importantly, this intervention improved muscle regeneration markers (p ≤ 0.05) without the unfavorable side effects seen with lipid infusion. Conclusions: Obesity-induced muscle protection during sepsis is partly mediated by elevated mobilization and metabolism of endogenous fatty acids. Furthermore, increased availability of ketone bodies, either through ketogenesis or through parenteral infusion, appears to protect against sepsis-induced muscle weakness also in the lean.

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A Comparison of the Effects of Skeletal Trauma and Surgery on the Ketosis of Starvation in Man

Cited by 59 publications

References 0 publications

Effect of withholding early parenteral nutrition in PICU on ketogenesis as potential mediator of its outcome benefit

Effect of withholding early parenteral nutrition in PICU on ketogenesis as potential mediator of its outcome benefit

Plasma Leptin, Energy Intake and Hunger following Total Hip Replacement Surgery

Adipose tissue protects against sepsis-induced muscle weakness in mice: from lipolysis to ketones

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