Iatrogenic hypoglycemia as a cause of hypoglycemia-associated autonomic failure in IDDM. A vicious cycle.

Three hypoglycemia-associated clinical syndromes in people with insulin-dependent diabetes mellitus (IDDM)--defective glucose counterregulation, hypoglycemia unawareness, and elevated glycemic thresholds for symptoms and activation of counterregulatory systems during effective intensive therapy--have much in common. They segregate together, are associated with increased frequency of severe iatrogenic hypoglycemia, and share several pathophysiological features, including reduced autonomic nervous system responses to a given degree of hypoglycemia. In the setting of reduced glucagon responses, the reduced adrenomedullary epinephrine responses play a key role in the pathogenesis of iatrogenic hypoglycemia in affected patients. Thus, these syndromes are examples of hypoglycemia-associated autonomic failure in IDDM, a disorder distinct from classical diabetic autonomic neuropathy. The pathogenesis of hypoglycemia-associated autonomic failure is not known, need not be the same in all three syndromes, and could be multifactorial even in a given syndrome. The recent finding that short-term antecedent hypoglycemia results in reduced symptomatic and autonomic (including adrenomedullary) responses to subsequent hypoglycemia in nondiabetic humans leads logically to the following hypothesis concerning one potential pathogenetic mechanism: recent antecedent iatrogenic hypoglycemia is a major cause of hypoglycemia-associated autonomic failure in IDDM, and hypoglycemia-associated autonomic failure, by reducing both symptoms of and defenses against developing hypoglycemia, results in recurrent severe hypoglycemia, thus creating a vicious cycle. If this hypothesis is confirmed, it will suggest strategies to reduce the frequency of iatrogenic hypoglycemia in people with IDDM.     

Sleep-related hypoglycemia-associated autonomic failure in type 1 diabetes: reduced awakening from sleep during hypoglycemia

Given that iatrogenic hypoglycemia often occurs during the night in people with type 1 diabetes, we tested the hypothesis that physiological, and the resulting behavioral, defenses against developing hypoglycemia-already compromised by absent glucagon and attenuated epinephrine and neurogenic symptom responses-are further compromised during sleep in type 1 diabetes. To do so, we studied eight adult patients with uncomplicated type 1 diabetes and eight matched nondiabetic control subjects with hyperinsulinemic stepped hypoglycemic clamps (glucose steps of approximately 85, 75, 65, 55, and 45 mg/dl) in the morning (0730-1230) while awake and at night (2100-0200) while awake throughout and while asleep from 0000 to 0200 in random sequence. Plasma epinephrine (P = 0.0010), perhaps norepinephrine (P = 0.0838), and pancreatic polypeptide (P = 0.0034) responses to hypoglycemia were reduced during sleep in diabetic subjects (the final awake versus asleep values were 240 +/- 86 and 85 +/- 47, 205 +/- 24 and 148 +/- 17, and 197 +/- 45 and 118 +/- 31 pg/ml, respectively), but not in the control subjects. The diabetic subjects exhibited markedly reduced awakening from sleep during hypoglycemia. Sleep efficiency (percent time asleep) was 77 +/- 18% in the diabetic subjects, but only 26 +/- 8% (P = 0.0109) in the control subjects late in the 45-mg/dl hypoglycemic steps. We conclude that autonomic responses to hypoglycemia are reduced during sleep in type 1 diabetes, and that, probably because of their reduced sympathoadrenal responses, patients with type 1 diabetes are substantially less likely to be awakened by hypoglycemia. Thus both physiological and behavioral defenses are further compromised during sleep. This sleep-related hypoglycemia-associated autonomic failure, in the context of imperfect insulin replacement, likely explains the high frequency of nocturnal hypoglycemia in type 1 diabetes.     

Limited impact of vigorous exercise on defenses against hypoglycemia: relevance to hypoglycemia-associated autonomic failure

Hypoglycemia-associated autonomic failure (HAAF)-reduced autonomic (including adrenomedullary epinephrine) and symptomatic responses to hypoglycemia caused by recent antecedent hypoglycemia-plays a key role in the pathogenesis of defective glucose counterregulation and hypoglycemia unawareness and thus iatrogenic hypoglycemia in type 1 diabetes. On the basis of the findings that cortisol infusion mimics and deficient or inhibited cortisol secretion minimizes this phenomenon, it has been suggested that the cortisol response to antecedent hypoglycemia mediates HAAF. We tested the hypothesis that any stimulus that releases cortisol, such as exercise, reduces autonomic and symptomatic responses to subsequent hypoglycemia. Thirteen healthy young adults (four women) were studied on three occasions in random sequence: 1) cycle exercise ( approximately 70% peak oxygen consumption) from 0830 to 0930 h and from 1200 to 1300 h on day 1 and hyperinsulinemic (2.0 mU x kg(-1) x min(-1)) stepped hypoglycemic (85, 75, 65, 55, and 45 mg/dl) clamps on day 2, 2) rest on day 1 and identical hypoglycemic clamps on day 2, and 3) hyperinsulinemic-euglycemic clamps. Exercise raised plasma cortisol concentrations to 16.9 +/- 1.9 (0930 h) and 16.6 +/- 1.6 microg/dl (1300 h) on day 1. Compared with rest on day 1, exercise on day 1 was associated with reduced epinephrine (P = 0.0113) responses-but not norepinephrine (P = 0.6270), neurogenic symptom (P = 0.6470), pancreatic polypeptide (P = 0.0629), or glucagon (P = 0.0436, but higher) responses-to hypoglycemia on day 2. However, the effect was small. (The final day 2 hypoglycemia epinephrine values were 765 +/- 106 pg/ml after rest on day 1 and 550 +/- 94 pg/ml after exercise on day 1 compared with 30 +/- 6 pg/ml during euglycemia.) These data are consistent with the hypothesis that the cortisol response to hypoglycemia mediates in part the reduced epinephrine response to subsequent hypoglycemia, one key component of HAAF in type 1 diabetes. However, the small effect suggests that an additional factor or factors may well be involved. These data do not support the hypothesis that the cortisol response to hypoglycemia mediates the reduced neurogenic symptom response to subsequent hypoglycemia, another key component of HAAF in type 1 diabetes.     

Antecedent hypercortisolemia is not primarily responsible for generating hypoglycemia-associated autonomic failure

Hypoglycemia-associated autonomic failure (HAAF) occurs commonly in patients with longstanding diabetes, placing affected patients at increased risk for severe hypoglycemia. Previous studies have suggested that hypoglycemia-induced hypercortisolemia may be responsible for blunting subsequent sympathoadrenal responses to hypoglycemia; however, this view remains highly controversial. In this work, we sought to better define the role of antecedent hypercortisolemia in generating HAAF, using two complimentary experimental models in nondiabetic human subjects: 1) antecedent hydrocortisone infusions (simulating physiologic cortisol responses to hypoglycemia) and 2) antecedent hypoglycemia, with and without concurrent blockade of endogenous cortisol production using oral metyrapone. Our results showed no effect of antecedent hypercortisolemia on epinephrine responses to subsequent hypoglycemia (area under the curve/time 280 +/- 53 vs. 337 +/- 57 pg/ml, P = 0.16). Of particular importance, selective blockade of endogenous cortisol production during antecedent hypoglycemia had no effect on subsequent counterregulatory responses to hypoglycemia. Compared with epinephrine responses following antecedent euglycemia (area under the curve/time 312 +/- 38 pg/ml), epinephrine responses were comparably blunted following antecedent hypoglycemia, regardless of whether concurrent metyrapone blockade was employed (198 +/- 28 vs. 192 +/- 28 pg/ml, P = NS). Similar results were obtained for glucagon and ACTH levels. Considered together, these observations provide strong evidence that hypoglycemia-induced hypercortisolemia is not primarily responsible for the generation of HAAF.     

Diabetic end-stage renal failure with autonomic dysfunction and spontaneous hypoglycemia during fasting

Spontaneous hypoglycemia during fasting was frequently observed in a 53-year old man with diabetic end-stage renal failure. On fasting, despite being managed on dietary therapy, this patient developed hypoglycemia (independent of hemodialysis), at which time he was lethargic. He showed severe autonomic dysfunction for a long period. No significant transient increase in catecholamines was not observed in response to the Schellong test or during the hypoglycemic episodes. During the oral glucose tolerance test (OGTT) and intravenous glucose tolerance test (IVGTT), basal insulin level was not detectable, and insulin response was absent. Glucagon loading test and epinephrine loading test suggested that the glycogen store in the liver was maintained, but that glycogenolysis was impaired. Lack of catecholamine response and diminished glucagon response to hypoglycemia because of autonomic disinnervation may suppress hepatic glycogenolysis and renal gluconeogenesis, thereby resulting in fasting hypoglycemia in pathologic situations such as diabetes mellitus and renal insufficiency. Received: August 6, 1999 / Accepted: October 14, 1999     

Epidural extension failure in obese women is comparable to that of non‐obese women

Background

Management of labor epidurals in obese women is difficult and extension to surgical anesthesia is not always successful. Our previous retrospective pilot study found epidural extension was more likely to fail in obese women. This study used a prospective cohort to compare the failure rate of epidural extension in obese and non‐obese women and to identify risk factors for extension failure.

Methods

One hundred obese participants (Group O, body mass index ≥ 40 kg/m²) were prospectively identified and allocated two sequential controls (Group C, body mass index ≤ 30 kg/m²). All subjects utilized epidural labor analgesia and subsequently required anesthesia for cesarean section. The primary outcome measure was failure of the labor epidural to be used as the primary anesthetic technique. Risk factors for extension failure were identified using Chi‐squared and logistic regression.

Results

The odds ratio (OR) of extension failure was 1.69 in Group O (20% vs. 13%; 95% CI: 0.88–3.21, P = 0.11). Risk factors for failure in obese women included ineffective labor analgesia requiring anesthesiologist intervention, (OR 3.94, 95% CI: 1.16–13.45, P = 0.028) and BMI > 50 kg/m² (OR 3.42, 95% CI: 1.07–10.96, P = 0.038).

Conclusion

The failure rate of epidural extension did not differ significantly between the groups. Further research is needed to determine the influence of body mass index > 50 kg/m² on epidural extension for cesarean section.     

Muscles that do not cross the knee contribute to the knee adduction moment and tibiofemoral compartment loading during gait

The aims of this study were to evaluate and explain the individual muscle contributions to the medial and lateral knee compartment forces during gait, and to determine whether these quantities could be inferred from their contributions to the external knee adduction moment. Gait data from eight healthy male subjects were used to compute each individual muscle contribution to the external knee adduction moment, the net tibiofemoral joint reaction force, and reaction moment. The individual muscle contributions to the medial and lateral compartment forces were then found using a least‐squares approach. While knee‐spanning muscles were the primary contributors, non‐knee‐spanning muscles (e.g., the gluteus medius) also contributed substantially to the medial compartment compressive force. Furthermore, knee‐spanning muscles tended to compress both compartments, while most non‐knee‐spanning muscles tended to compress the medial compartment but unload the lateral compartment. Muscle contributions to the external knee adduction moment, particularly those from knee‐spanning muscles, did not accurately reflect their tendencies to compress or unload the medial compartment. This finding may further explain why gait modifications may reduce the knee adduction moment without necessarily decreasing the medial compartment force. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1586–1595, 2012     

Role for autonomic nervous system to increase pancreatic glucagon secretion during marked insulin-induced hypoglycemia in dogs.

To determine the role of the autonomic nervous system (ANS) in mediating the glucagon response to marked insulin-induced hypoglycemia in dogs, we measured arterial and pancreatic venous glucagon responses to insulin-induced hypoglycemia during acute, terminal experiments in halothane-anesthetized dogs in which the ANS was intact (control; n = 9), pharmacologically blocked by the nicotinic ganglionic antagonist hexamethonium (n = 6), or surgically ablated by cervical vagotomy and cervical spinal cord section (n = 6). In control dogs, insulin injection caused plasma glucose to fall by 4.4 +/- 0.2 mM to a nadir of 1.7 +/- 0.2 mM. Arterial epinephrine (EPI) levels increased by 13,980 +/- 1860 pM (P less than 0.005), confirming marked activation of the ANS. Pancreatic output of glucagon increased from 0.53 +/- 0.12 to 2.04 +/- 0.38 ng/min during hypoglycemia (change [delta] +1.51 +/- 0.33 ng/min, P less than 0.005). This increased arterial plasma glucagon from 27 +/- 3 to 80 +/- 15 ng/L (delta +52 +/- 14 ng/L, P less than 0.025). Hexamethonium markedly reduced the ANS response to insulin injection (delta EPI +2130 +/- 600 pM, P less than 0.025 vs. control) despite a similar fall of plasma glucose (delta -4.1 +/- 0.2 mM) and a lower nadir (0.6 +/- 0.1 mM). Both the pancreatic glucagon response (delta glucagon output +0.45 +/- 0.2 ng/min) and the arterial immunoreactive glucagon response (delta +5 +/- 4 ng/L) were substantially reduced by hexamethonium (P less than 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)     

Portal vein glucose sensors do not play a major role in modulating physiological responses to insulin-induced hypoglycemia in humans

OBJECTIVE—Experimental data from animal studies indicate that portal vein glucose sensors play a key role in the responses to slow-fall hypoglycemia. However, their role in modulating these responses in humans is not well understood. The aim of the present study was to examine in humans the potential role of portal vein glucose sensors in physiological responses to insulin-induced hypoglycemia mimicking the slow fall of insulin-treated diabetic subjects.RESEARCH DESIGN AND METHODS—Ten nondiabetic subjects were studied on two different occasions during intravenous insulin (2 mU · kg⁻¹ · min⁻¹) plus variable glucose for 160 minutes. In both studies, after 60 min of normal plasma glucose concentrations, hypoglycemia (47 mg/dl) was induced slowly (60 min) and maintained for 60 min. Hypoglycemia was preceded by the ingestion of either oral placebo or glucose (28 g) given at 30 min.RESULTS—Plasma glucose and insulin were not different with either placebo or glucose (P > 0.2). Similarly, counterregulatory hormones, substrates, and symptoms were not different with either placebo or glucose. The Stroop color and colored words subtest of the Stroop test deteriorated less (P < 0.05) with glucose than placebo.CONCLUSIONS—In contrast to animals, in humans, prevention of portal hypoglycemia with oral glucose from the beginning of insulin-induced slow-fall hypoglycemia has no effect on sympathoadrenal and symptomatic responses to hypoglycemia.It has been suggested that glucose sensors in the portal area are necessary to monitor glucose derived from the gut (1). In fact, when exogenous glucose is infused directly in the portal vein (2,3) or in the duodenum (4) or ingested orally as glucose load (5–7), a portal-arterial glucose gradient is generated with glucose concentrations higher in the portal vein than in arterial circulation. Such portal-arterial glucose gradient generates a portal signal that is probably dependent on glucose-sensitive nerves in the portal veins, the firing rate of which is inversely proportional to the portal glucose concentration (8). The signal then moves through the hepatic vagal afferences to modulate the function of different tissues (e.g., liver, pancreatic β-cells) involved in the control of glucose homeostasis (9). In addition, signals enter the central nervous system to regulate hypothalamic functions, such as feeding and satiety (10). Recent evidence indicates that GLUT2 transporter is essential for glucose sensing by the portal glucose sensor (11,12) and also that glucagon-like peptide 1 (GLP-1) receptor is required for the function of the portal glucose sensor in mice (9).Earlier studies in animals have shown that portal-arterial glucose gradient is involved in the control of intake of food (10) and stimulation of net hepatic glucose uptake (2,13). In addition, portal glucose sensors modulate the sympathetic responses to hypoglycemia (14,15). However, how portal glucose sensors may affect sympathetic responses to hypoglycemia and how their activity integrates with that of glucose-sensitive areas in the brain is not well understood (16). In fact, several studies in animals indicate that the brain is the prominent center for the sensing of hypoglycemia. In dogs in which insulin-induced hypoglycemia was allowed to occur peripherally while brain euglycemia was maintained by glucose infusions in carotid and vertebral arteries bilaterally, the responses of counterregulatory hormones decreased nearly completely compared with dogs with brain neuroglycopenia (17,18). In rats, the ventromedial hypothalamus (VMH) appears to be necessary to trigger counterregulation during hypoglycemia. In fact, bilateral lesions of the VMH in conscious rats suppresses glucagon and catecholamine responses during hypoglycemia (19,20), suggesting that the VHM is one of the most important sites acting as a glucose sensor (21,22). However, there is evidence that in rats, activation of portal glucose sensors by glucose may be the most important modulators of sympathetic response to hypoglycemia, resulting in a significant suppression of this response (23–25).Recent studies in rats have established that portal vein glucose sensors, responsible for hypoglycemic detection, extend beyond the portal vein being placed also in the superior mesenteric vein and that their role is essential in detecting slow, but not fast, fall in blood glucose (26).Limited knowledge is available about the potential role of portal glucose sensors in humans. Only three studies (5–7) have addressed the question, with conflicting results. In fact, counterregulatory hormone responses to hypoglycemia have been found potentiated (5), reduced (6), or reduced in early phase and potentiated in late phase (7) after ingestion of oral glucose (5,6) or orange juice (7). It is likely that methodological differences account, at least in part, for these divergent results.So far, no study has investigated in humans the role of portal glucose sensors on counterregulation, symptoms, and cognitive function during hypoglycemia induced slowly, to mimic the hypoglycemia of the clinical situation (27). It is worthy of note that in the postprandial state, a condition characterized by glucose arriving in the portal vein from the gut, sympathetic responses and some aspects of cognitive function are affected by the rate of fall of blood glucose (27). However, in the postprandial condition, it is not only glucose that enters in the portal system but also other substrates that may suppress sympathoadrenal responses to hypoglycemia (28).The aim of the present study was to examine in humans the potential effects of portal glucose sensors on hormonal counterregulatory responses and responses of symptoms and cognitive function in a model of slow-fall insulin-induced hypoglycemia. For this purpose, healthy subjects were studied during hypoglycemia preceded by ingestion of either oral glucose to prevent portal hypoglycemia or placebo.     

Malignant hypertension secondary to renovascular disease during infancy--an unusual cause of failure to thrive

An 11-month-old girl presented with a history of failure to thrive, vomiting, polydipsia, polyuria and visual inattention. She was found to have malignant hypertension due to unilateral renal artery stenosis. This was successfully treated with percutaneous transluminal balloon angioplasty. Nearly 10 years following this initial presentation, she remains normotensive on no anti-hypertensive medications.     

Peritoneal pH during laparoscopy is dependent on ambient gas environment: helium and nitrous oxide do not cause peritoneal acidosis

Background Little is know about the effects of different insufflation gases on peritoneal pH during laparoscopy. However, these changes may influence the intracellular signalling system, resulting in altered cell growth or adhesiveness. The aim of this study was to determine the effects of carbon dioxide (CO₂), nitrous oxide (N₂O), and helium (He) on parietal and visceral peritoneal pH. The effect of different intraabdominal pressures on parietal and visceral peritoneal pH was also examined.Methods We conducted both an ambient gas study and a pressure study. For the ambient gas study, 20 pigs were divided into the following four groups: (a) CO₂, (b) He, (c) N₂O, and (d) abdominal wall lift (Lift) laparoscopy. Parietal and visceral peritoneal pH were measured at 15 min intervals for 180 min. For the pressure study, 15 pigs were divided into the following three groups: (a) CO₂, (b) He, (c) N₂O laparoscopy. Baseline values were established for parietal and visceral peritoneal pH. Intraabdominal pressure was then increased stepwise at 1-mmHg intervals to 15 mmHg. After pressure was maintained for 15 min at each setting, parietal and visceral peritoneal pH were measured.Results Ambient gas environment was the major determinant of parietal peritoneal pH. Carbon dioxide caused parietal peritoneal acidosis. Helium, N₂O, and Lift caused alkalotic parietal peritoneal pH. Intraabdominal pressure had a minor effect on parietal peritoneal pH. At higher intraabdominal pressure (12–15 vs 5–8 mmHg), CO₂ caused a slight decrease in parietal peritoneal pH, whereas N₂O and He caused a slight increase in parietal peritoneal pH. Visceral peritoneal pH remained relatively unaffected during all studies.Conclusions Parietal peritoneal pH during laparoscopy was highly dependent on the ambient gas environment. The effect of intraabdominal pressure on parietal peritoneal pH was of minor significance. Carbon dioxide caused a slight worsening of parietal peritoneal acidosis at higher intraabdominal pressure, whereas, N₂O, He, and Lift did not cause parietal peritoneal acidosis.     

In vitro low-speed side collisions cause injury to the lower cervical spine but do not damage alar ligaments

Whether injuries to the alar ligaments could be responsible for complaints of patients having whiplash injury in the upper cervical spine is still controversially discussed. It is known that these ligaments protect the upper cervical spine against excessive lateral bending and axial rotation movements. The objective of the present in vitro study was therefore to examine whether the alar ligaments or any other structures of the cervical spine are damaged in side collisions. In a specially designed acceleration apparatus, six human osteoligamentous cervical spine specimens were subjected to incremental 90° side collisions from the right (1 g, 2 g, 3 g, etc.) until structural failure occurred. A damped pivot table accounted for the passive movements of the trunk during collision, and a dummy head (4.5 kg) ensured almost physiological loading of the specimens. For quantification of functional injuries, the three-dimensional flexibility of the specimens was tested in a spine tester before and after each acceleration. In all six specimens, structural failure always occurred in the lower cervical spine and always affected the facet joint capsules and the intervertebral discs. In four specimens, this damage occurred during the 2 g collision, while in the other two it occurred during the 3 g and 4 g collision, respectively. The flexibility mainly increased in the lower cervical spine (especially in lateral bending to both sides) and, to a minor extent, in axial rotation. In vitro low-speed side collisions caused functional and structural injury to discoligamentous structures of the lower cervical spine, but did not damage the alar ligaments. Since the effects of muscle forces were not taken into account, the present in vitro study reflects a worst-case scenario. Injury thresholds should therefore not be transferred to reality.