When glucose needs exceed 12mg/kg/min, glucocorticoid therapy is an option,, due to stimulation of neoglucogenesis and reduction in peripheral glucose utilization. Hydrocortisone (5mg/kg/day divided in two doses orally or intravenously) or prednisone (2mg/kg/day orally or intravenously) are used over several days until glycaemia recovers and doses can be gradually decreased. In this scenario (persistently high needs of exogenous glucose administration, despite glucocorticoid treatment) or in emergency situations where glucose bolus alone is not effective or cannot be administered rapidly enough, glucagon is an alternatively, though infrequently used. A wide rang of initial bolus doses have been reported, but in a recent review, the suggested initial dose is 0.2-0.3 mg/kg (either intramuscular administration or as a slow intravenous push over one minute) with a maximum doses of 1mg. Blood glucose should rise in the next 20-30 minutes. If not, another does can be administered, and if there is still no response, glycogen store disorders must be ruled out. This is only a temporary option, while interventions are planned to provide sufficient glucose and to start diagnosis of hyperinsulinism which may prompt use of

There is increasing concern about neurodevelopment after hypoglycaemia and many studies have tried to establish a correlation between hypoglycaemia and brain damage, dating since the 1960´s. But, to date there is still not sufficient adequate information to define a precise cut-off glucose value, below which irreversible brain damage occurs, at a specific moment or for a defined period of time, in a given infant or in a subset of specific infants. There seems to be consensus that it is after recurrent, protracted, severely low glucose concentrations (less than 18-20mg/dL (< 1mmol/L) for more that 1-2 hours) specially when accompanied by severe neurological symptoms such as seizures or coma, that adverse neurological outcome is to be expected (Rozance & Hay,2006; Cornblath, 2000; Alkalay, 2005; Vannuci, 2001). There is also consensus that in order to define CNS injury as a consequence of hypoglycaemia, other obvious CNS lesions must be absent (such as hypoxiaischemia, intracranial haemorrhage, infection, etc.). Other conditions such as confirmed or suspected hyperinsulinemic hypoglycaemia in the presence of seizures, for example,

Because we do not know what the absolute threshold value is, operational thresholds have been suggested, where clinical guidance is compulsory, so an infant with neurological symptoms will need more urgent evaluation than an asymptomatic newborn, regardless of

In the preterm population, there are no conclusive studies regarding neurological outcome in case of hypoglycaemia, but they suggest that even mild but repeated hypoglycaemia could be detrimental on brain development. Retrospective data from a multicenter trial of

contribute to the diagnosis of hypoglycaemic injury (Rozance & Hay, 2006).

hyperinsulinism due to direct pancreatic stimulus, and further hypoglycaemia.

diazoxide or somatostatin as mentioned earlier (Chan, 2011).

**9. Neurological outcome**

the glucose value (Williams, 2005).

nutrition in premature infants found lower Bayley mental and psychomotor scores at 18 months in infants with at least five confirmed hypoglycaemia events, with a higher rate of developmental delay and cerebral palsy, but however failed to confirm these findings at 7.5 and 8 years of age (Lucas et al, 1988; Cornblath, 1999 as cited in Chan, 2011).

Considering the innate risk for adverse neurodevelopment in the preterm infant, emphasis must be put on monitoring glucose levels in these infants to avoid further possible CNS injury (Wayenberg & Pardou, 2008).

It is worth pointing out that the physiopathological mechanisms that promote injury in hypoglycaemia vary from injury mechanisms in HIE, with some areas being more sensitive to deprivation of glucose and others to deprivation of oxygen and a greater tendency towards selective neuronal necrosis in hypoglycaemic babies. Also, concurrent hypoglycaemia and HIE have worst prognosis than either condition individually, therefore extreme caution must be taken to maintain normoglycaemia in an HIE setting (Vannuci, 2001; Garg & Devaskar, 2006).

Neonatal hypoglycaemia can lead to reduced head circumference at follow-up, lower psychomotor scores, motor deficit and mental retardation. Specifically neonates with recurrent episodes had lower psychomotor scores than those with a single episode. (Lucas, 1988; Nunes, 2000; Greery, 1966 as cited in Alkalay 2005).

Hypoglycaemia episodes with seizures have worse outcomes than hypoglycaemia episodes alone. At follow-up, many of those that had hypoglycaemia and seizures develop epilepsy of different types such as infantile spasms and partial seizures. Electroencephalographic recordings do not show specific patognomonic features that may result diagnostic (Alkalay, 2005).

Parieto-occipital diffusion restriction seen on MRI scans have been reported associated with neonatal hypoglycaemia and can result in long-term disability, epilepsy, and visual impairment (Finlan et al, 2006; Tam et al, 2008). The aetiology of this pattern of injury is unclear; however, transient hyperinsulinism may be an independent risk factor. Magnetic resonance brain imaging can help define the extent of brain injury and guide follow-up. In a 23 case follow-up, with severely low and persistent or recurrent glucose values, abnormal brain imaging findings were associated with profound hypoglycaemia and involved occipital lobes in 82% the cases. Half of these infants had visual impairment (Alkalay et al, 2005b).

In relation to this, a cohort of 45 neonates with diffusion-weighted MRI studies after hypoglycaemia was studied retrospectively to determine whether hypoglycaemic injury, as indicated by diffusion restriction in the occipital lobes, correlated with visual evoked potentials and long-term cortical visual dysfunction. They saw that diffusion-weighted imaging studies performed within 6 days after initial hypoglycaemia were sensitive in term (50% had restricted diffusion in occipital lobes) but not in preterm neonates (none had this alteration), as opposed to those performed after, and were associated with abnormal visual evoked potentials detected within 1 week after birth. Cortical visual impairment happened in a signicant proportion of patients with recurrent hypoglycaemia and correlated significantly with low mesial occipital apparent diffusion coefcient values. They concluded that diffusion restriction, with low apparent diffusion coefcient values, in the mesial occipital poles, may indicate poor visual outcomes in acute settings after neonatal hypoglycaemia (Tam et al, 2008).

While occipital lobe injury patterns have been widely described, other brain injury patterns have also been identified when studying MRI scans performed on term neonates with

Neonatal Hypoglycemia - Current Concepts 101

In the setting of persistent hypoglycaemia, persistent hyperinsulinemic hypoglycaemia, inborn errors of metabolism and endocrine disorders must be ruled out. Specifically, when considering persistent hyperinsulinemic hypoglycaemia, innovations in diagnosis at a molecular and radiological level have been particularly important in terms of differentiating focal from diffuse forms, which, if unresponsive to medical treatment may be candidates for

Achoki, R., Opiyo, N., English, M. (2010). Mini-revie : Management of hypoglycaemia in

Alkalay, AL., Flores-Sarnat, L. Sarnat, HB et al. (2005b).Brain imaging findings in neonatal

Arnoux, JB., De Lonlay, P., Hussain, K., et al. (2010). Congenital hyperinsulinism. Eraly

Beardsall, K. (2010). Measurement of glucose levels in the newborn. Early Human Delivery,

Burns, CM., Rutherford, MA., Boardman, JP. (2008). Patterns of cerebral injury and

Chan, SW. (2011; last updated February 2011). Neonatal hypoglycaemia, in: *Up to Date reviews.* Available at: www.uptodate.com/contents/neonatal-hypoglycemia Cornblath, M. & Hawdon, JM. (2000). Controversies regarding definition of neonatal

Diderholm, B. (2009). Perinatal energy metabolism with reference to IUGR & SGA: Studies

Desphande, S., Ward Plat, M. (2005). The investigation and management of neonatal

Fernández Lorenzo, JR., Pico Couce, M., Fraga Bermúdez, JM. (2011). Hipoglucemia

Filan, PM., Inder, TE., Cameron, FK. et al. (2006). Pediatrics Vol.148, No.4. (April 2006) pp:

Fugelseth, D. (2001). Neonatal hypglycemia. Dsskr Nor Laegeforen Vol.121, No.14 (May

Garg, M. & Devaskar, SU. (2006). Glucose metabolsim in the late preterm infant. Clinical

Giurgea, I., Ribeiro, MJ., Boddaert, N., et al. (2005). Congenital hyperinsulinism in newborn and infant. Archives de Pediatrie Vol.12, No.11 (November 2005) pp:1628-35 Gustaffson, J. (2009). Neonatal energy substrate production. Indian Journal Medical

227-34. doi:10.1093/tropej/fmp109. Available on PMC October 2010. Alkalay, AL., Sarnat, HB., Flores-Sarant, L. et al.(2005a). Neurologic aspects of neonatal

(Philadelphia) Vol.44, No.9 (November-December 2005) pp: 783-90.

hypoglycemia. IMAJ Vol.7 (March 2005) pp:188-191

Human Delivery. Vol.86, No.5 (June 2010) pp: 287-94

Vol.86, No.5 (June 2010). pp: 263-7

Pediatrics Vol.122 pp: 65-74

(Novembre 2009) pp: 612-17

ISBN 978-84-8473-908-1, Madrid, Spain.

Perinatology Vol.33, No.4 (December 2006) pp: 853-70

Research, Vol.130 (November 2009) pp: 618-23

2005) pp: 351-61.

2001) pp: 1713-6

552-4

children 0-59 months. Journal Tropical Pediatrics, Vol. 56, No.4 (August 2010), pp.

hypoglycemia : case report and review of 23 cases. Clinical Pediatrics

neurodevelopmental outcomes after symptomatic neonatal hypoglycaemia.

hypoglycaemia: suggested operational thresholds. Pediatrics Vol.105, No.5 pp: 1141-5

in pregnant women & newborn infants. Indian Journal Medical Research, Vol.130

hypoglycaemia. Seminars in Fetal and Neonatal Medicine, Vol.10, No.4 (August

neonatal, in *Protocolos Diagnóstico-terapéuticos de neonatología de la SEN-AEP*, Ergon,

curative partial pancreatectomy.

**12. References**

symptomatic hypoglycaemia and compared to neurologically normal infants. White matter abnormalities occurred in 94% of the infants (43% of theses were severe lesions), with predominant posterior lobe alterations in 29% of the cases. Cortical abnormalities were identified in 51% of infants; 30% had white matter haemorrhage, 40% basal ganglia and or thalamic lesions, and 11% had an abnormal posterior limb of the internal capsule. Three infants had middle cerebral artery territory infarctions. It was noted that early MRI ndings predicted neurodevelopmental outcomes better than the severity or duration of hypoglycaemia: 65% of these infants had impaired neurologic development at 18 months, which were related to the severity of white matter injury and involvement of the posterior limb of the internal capsule (Burns et al, 2008).

#### **10. Prevention**

Despite controversy and gaps in knowledge as to what level of hypoglycaemia and for how long, brain injury occurs, it is clear that hypoglycaemia can and must be prevented. In the majority of healthy newborn infants, if hypoglycaemia occurs, it is merely a transient adaptation process. However, although the majority of term newborns without risk factors will adapt correctly, there is up to 10% of these infants that will have significant hypoglycaemia in the first 3-4 hours of life, and will probably be asymptomatic. Helping these infants adapt is best achieved when promoting early skin to skin contact as soon as the baby is born (this promotes mother-child bonding, more effective breast feeding and better temperature control) and early and frequent breast feeding. On the other hand, infants with risk for hypoglycaemia are more vulnerable and may not adapt as easily as a healthy newborn, despite applying these strategies. Preventing significant hypoglycaemia in this subset population implies controlling these infants at risk in the first hours of life and thereafter periodically depending on the infants' clinical status and glucose levels, and adapting treatment options to the babies' situation.

#### **11. Conclusions**

Hypoglycaemia in the neonatal period is a frequent problem. In the majority of cases, in healthy term newborns, it is merely a transient adaptation process from intra-uterine life to extra-uterine conditions. However, there are infants who for different reasons are at risk of more significant and persistent hypoglycaemia, that will have less capacity to adapt to extrauterine life and that will require frequent monitoring and treatment when necessary.

The goal is to maintain normoglycaemia in order to assure an adequate energy substrate for all organs but most importantly for the brain in order to prevent brain injury. To achieve this, many cut-off values have been proposed, and perhaps the most accepted concept is that of defining specific "operational thresholds" for different groups of infants at risk, that is, the glucose value for a given infant where treatment is required, the point where we must intervene. There is consensus in the need of preventing hypoglycaemia, which means looking out for it in infants at risk, and promptly treating it if present (from more frequent feeding to parenteral glucose infusion to glucagon if necessary).

Hypoglycaemic induced brain damage occurs when hypoglycaemia is severely low in a persistent or recurrent manner, and is more likely when acute neurological symptoms such as seizures are present. Occipital lobe affectation has been widely described, but recent research opens the scope of brain injury to white matter and to vascular lesions as well.

In the setting of persistent hypoglycaemia, persistent hyperinsulinemic hypoglycaemia, inborn errors of metabolism and endocrine disorders must be ruled out. Specifically, when considering persistent hyperinsulinemic hypoglycaemia, innovations in diagnosis at a molecular and radiological level have been particularly important in terms of differentiating focal from diffuse forms, which, if unresponsive to medical treatment may be candidates for curative partial pancreatectomy.

#### **12. References**

100 Hypoglycemia – Causes and Occurrences

symptomatic hypoglycaemia and compared to neurologically normal infants. White matter abnormalities occurred in 94% of the infants (43% of theses were severe lesions), with predominant posterior lobe alterations in 29% of the cases. Cortical abnormalities were identified in 51% of infants; 30% had white matter haemorrhage, 40% basal ganglia and or thalamic lesions, and 11% had an abnormal posterior limb of the internal capsule. Three infants had middle cerebral artery territory infarctions. It was noted that early MRI ndings predicted neurodevelopmental outcomes better than the severity or duration of hypoglycaemia: 65% of these infants had impaired neurologic development at 18 months, which were related to the severity of white matter injury and involvement of the posterior

Despite controversy and gaps in knowledge as to what level of hypoglycaemia and for how long, brain injury occurs, it is clear that hypoglycaemia can and must be prevented. In the majority of healthy newborn infants, if hypoglycaemia occurs, it is merely a transient adaptation process. However, although the majority of term newborns without risk factors will adapt correctly, there is up to 10% of these infants that will have significant hypoglycaemia in the first 3-4 hours of life, and will probably be asymptomatic. Helping these infants adapt is best achieved when promoting early skin to skin contact as soon as the baby is born (this promotes mother-child bonding, more effective breast feeding and better temperature control) and early and frequent breast feeding. On the other hand, infants with risk for hypoglycaemia are more vulnerable and may not adapt as easily as a healthy newborn, despite applying these strategies. Preventing significant hypoglycaemia in this subset population implies controlling these infants at risk in the first hours of life and thereafter periodically depending on the infants' clinical status and glucose levels, and

Hypoglycaemia in the neonatal period is a frequent problem. In the majority of cases, in healthy term newborns, it is merely a transient adaptation process from intra-uterine life to extra-uterine conditions. However, there are infants who for different reasons are at risk of more significant and persistent hypoglycaemia, that will have less capacity to adapt to extrauterine life and that will require frequent monitoring and treatment when necessary.

The goal is to maintain normoglycaemia in order to assure an adequate energy substrate for all organs but most importantly for the brain in order to prevent brain injury. To achieve this, many cut-off values have been proposed, and perhaps the most accepted concept is that of defining specific "operational thresholds" for different groups of infants at risk, that is, the glucose value for a given infant where treatment is required, the point where we must intervene. There is consensus in the need of preventing hypoglycaemia, which means looking out for it in infants at risk, and promptly treating it if present (from more frequent

Hypoglycaemic induced brain damage occurs when hypoglycaemia is severely low in a persistent or recurrent manner, and is more likely when acute neurological symptoms such as seizures are present. Occipital lobe affectation has been widely described, but recent research opens the scope of brain injury to white matter and to vascular lesions as well.

limb of the internal capsule (Burns et al, 2008).

adapting treatment options to the babies' situation.

feeding to parenteral glucose infusion to glucagon if necessary).

**10. Prevention**

**11. Conclusions**

**7**

*Finland*

**Glucose Infusions into Peripheral**

Outi Tammela and Tarja Vanhatalo

*Pediatric Research Centre, University of Tampere*

**Veins in Neonates with Hypoglycemia**

Intravenous glucose infusions into peripheral veins are often needed, in addition to oral feedings, to elevate blood glucose levels in the management of neonatal hypoglycemia. Central venous catheters are rarely inserted, when the duration of such treatment is less than a few days. More than half of peripheral venous cannulations extravasate by 36 h, or even faster, if medication is administered concomitantly (Möller et al., 1996, Hecker et al., 1991). Complications, including local swelling and in the worst cases damage to tissue may occur. Intravenous solutions containing 10 or 15 percent glucose are most commonly used in hypoglycemic infants. A glucose concentration of 15% has generally been regarded as the highest acceptable for use in solutions infused into peripheral veins in neonates. (Kien, 1993). However, 10% and even 15% glucose infusions increase fluid load especially in patients, who need high glucose intakes to reach sufficient energy intake or to maintain normal plasma glucose levels. Although large fluid volumes of short duration are well tolerated in neonates (Leake, et al, 1976), the effect of continuous rapid infusions on the fluid clearance have not been determined. First voiding might be delayed due to elevated Arginine vasopressin levels in newborn infants delivered vaginally after a prolonged and stressful labor (Vuohelainen T et al., 2007 and 2008). A poor fluid tolerance during the first days of life can be anticipated and cautious fluid administration might be indicated

Earlier studies suggest that the development of phlebitis does not depend so much on the osmolarity of the solution as other factors causing phlebitis, for example material of the catheter (Madan et al., 1992). Factors affecting the development of infusion phlebitis include vein characteristics, size and material of the catheter, duration of infusion and the osmolarity and pH of the infusion solution. Experimental infusions of 10% glucose with electrolytes (pH 4.93, osmolarity 727 mOsm/kg) into rabbit ear veins cause phlebitis by reason of its acidity and an infusion of amino acids (pH 6.29, osmolarity 929 mOsm/kg) by reason of its high osmolarity. On the other hand, admixture of these solutions causes only minor phlebitic changes and the fluid components eliminate each others' damaging effects on the tissue (Kuwahara et al., 1998a). In the same animal model, the tolerance of peripheral venous endothelial cells was for 8 h in 820 mOsm/kg, 12 h in 690 mOsm/kg and 24 h in 550 mOsm/kg solutions, respectively, suggesting that a planned volume of solutions with high osmolarity should be infused rapidly rather than slowly to avoid the development of phlebitis (Kuwahara et al. 1998b). In the management of hypoglycemia, however, only continuous

**1. Introduction**

especially in such infants.

### **Glucose Infusions into Peripheral Veins in Neonates with Hypoglycemia**

Outi Tammela and Tarja Vanhatalo *Pediatric Research Centre, University of Tampere Finland*

#### **1. Introduction**

102 Hypoglycemia – Causes and Occurrences

Hay Jr, WW., Raju, TN., Higgins, RD., Kalhan, SC., Devaskar, SU. (2009). Knowledge gaps and

Development. Journal Pediatrics, Vol.155, No.5 (Novembre 2009) pp: 612-7. Hussain, K., Blankenstein, O., De Lonlay, P., Christesen, T. (2007). Hyperinsulinaemic

(Kalhan, S. & Peter-Wohl, S. (2000). Hypoglycemia: what is it for the neonate? American

Kapoor, RR., James, C., Hussain, K. (2009a) Advances in the diagnosis and management of

Kapoor, RR., Flanagan, SE., James, C. et al. (2009b). Hyperinsulinaemic hypoglycaemia.

Mitanchez, D. (2007). Glucose regulation in preterm newborn infants. Hormone Research

Mitanchez, D. (2008). Ontogenesis of glucose regulation in neonate and consequences in

Simmons, RA. (2007). Glucose metabolism in the newborn infant, in *Workbook in Practical*

Rozance, PJ. &Hay Jr, WW. (2006). Hypoglycemia in newborn infants: features associated

Rozane, PJ % Hay Jr, WW. (2010). Describing hypoglycemia- Definition or operational threshold? Early Human Delivery, Vol.86, No.5 (May 2010) pp: 275-80. Straussman, S., Levitsky, LL. (2010). Neonatal hypoglycaemia. Current Opinion Endocrinology Diabetes Obseity Vol.17, No.1 (February 2010) pp: 20-4. Tam, EWY., Widjaja, E., Blase, SI. Et al. (2008). Occipital lobe injury and cortical visual outcomes after neonatal hypoglycaemia. Pediatrics Vol.122 pp: 507-12 Vannucci, RC. & Vannucci, SJ. (2001). Hypoglycemic brain injury. Seminars in Neonatology

Ward Platt, M., Desphande, S. (2005). Metabolic adaptation at birth. Seminars in Fetal and

Wayenberg, JL. & Pardou, A. (2008). Moderate hypoglycaemia in preterm infant: is it

Wight, NE. (2006). Hypoglycemia in breastfed neonates. Breastfeed Medicine Vol.1, No.4

Wilker, RE. (2004). Hipoglucemia e hiperglucemia, in *Manual de Cuidados Neonatalesr,* John P.

Williams, AF. (2005). Neonatal Hypoglycaemia: clinical and legal aspects. Seminars in Fetal

Cloherty & Ann R. Stark, pp. 615-623, Masson, ISBN 84-458-0740-4, Barcelona, Spain.

Archives Disease Childhood Vol.94, No.6 (June 2009) pp: 450-7

with adverse outcomes. Biology Neonate. Vol.92, No.2 pp: 74-8

Neonatal Medicine Vol.10, No.4 (August 2005) pp: 341-50

and Neonatal Medicine Vol.10, o.4 (August 2005) pp: 363-48

8- doi: 10.1136/adc.2007.116327

Journal Perinatology Vol.17, No.1 pp: 11-8

Metabolism Vol.5, No.2 (February 2009) pp: 101-12

Vol.68, (June 2007) pp: 265-71. doi: 10.1159/000104174

ISBN 978-1-4160-2637-2, Unites States of America.

Vol.6, No.2 (April 2001) pp: 147-55

(winter 2006) pp: 253-62

relevant? H Pediatrie Vol.15, No.2 pp: 153-6

research needs for understanding and treating neonatal hypoglycaemia: workshop report from Eunice Kennedy Shriver National Institute of Child Health and HUmand

hypoglycaemia : biochemical basis and the importance of maintaining normoglycaemia during management. Archives Disease Childhood Vol.92, pp: 567-

hyperinsulinemic hypoglycemia. Natural Clinical Practice Endocrinology

neonatal management. Archives de Pediatrie Vol.15, No.1 (January 2008) pp: 64-74.

*Neonatology,* Richard A. Polin & Mervin C. Yoder, pp. 45-52, Saunders Elsevier,

Intravenous glucose infusions into peripheral veins are often needed, in addition to oral feedings, to elevate blood glucose levels in the management of neonatal hypoglycemia. Central venous catheters are rarely inserted, when the duration of such treatment is less than a few days. More than half of peripheral venous cannulations extravasate by 36 h, or even faster, if medication is administered concomitantly (Möller et al., 1996, Hecker et al., 1991). Complications, including local swelling and in the worst cases damage to tissue may occur. Intravenous solutions containing 10 or 15 percent glucose are most commonly used in hypoglycemic infants. A glucose concentration of 15% has generally been regarded as the highest acceptable for use in solutions infused into peripheral veins in neonates. (Kien, 1993). However, 10% and even 15% glucose infusions increase fluid load especially in patients, who need high glucose intakes to reach sufficient energy intake or to maintain normal plasma glucose levels. Although large fluid volumes of short duration are well tolerated in neonates (Leake, et al, 1976), the effect of continuous rapid infusions on the fluid clearance have not been determined. First voiding might be delayed due to elevated Arginine vasopressin levels in newborn infants delivered vaginally after a prolonged and stressful labor (Vuohelainen T et al., 2007 and 2008). A poor fluid tolerance during the first days of life can be anticipated and cautious fluid administration might be indicated especially in such infants.

Earlier studies suggest that the development of phlebitis does not depend so much on the osmolarity of the solution as other factors causing phlebitis, for example material of the catheter (Madan et al., 1992). Factors affecting the development of infusion phlebitis include vein characteristics, size and material of the catheter, duration of infusion and the osmolarity and pH of the infusion solution. Experimental infusions of 10% glucose with electrolytes (pH 4.93, osmolarity 727 mOsm/kg) into rabbit ear veins cause phlebitis by reason of its acidity and an infusion of amino acids (pH 6.29, osmolarity 929 mOsm/kg) by reason of its high osmolarity. On the other hand, admixture of these solutions causes only minor phlebitic changes and the fluid components eliminate each others' damaging effects on the tissue (Kuwahara et al., 1998a). In the same animal model, the tolerance of peripheral venous endothelial cells was for 8 h in 820 mOsm/kg, 12 h in 690 mOsm/kg and 24 h in 550 mOsm/kg solutions, respectively, suggesting that a planned volume of solutions with high osmolarity should be infused rapidly rather than slowly to avoid the development of phlebitis (Kuwahara et al. 1998b). In the management of hypoglycemia, however, only continuous

Glucose Infusions into Peripheral Veins in Neonates with Hypoglycemia 105

The group allocation of each patient was written in a sealed envelope, which was opened after the written consent was received from the parents. Because infusion rates were dependent on

The infants' plasma glucose levels were measured every 4 h and the infusion rate reduced after each measurement by 0.5 mL/kg/h at blood glucose levels between 3.5–4 mmol/L and by 1 mL/kg/h at blood glucose levels above 4 mmol/L. The infusion was stopped when the plasma glucose level was 3.5 mmol/L or higher at an infusion rate of 2 mL/h. Plasma glucose surveillance was continued, until levels had remained normal (more than 2.9 mmoL/L) for 24 h after discontinuation of the glucose infusion. When the cannulation site had to be changed, local signs of phlebitis at the previous site were scored from 0 to 3 using a modified Maddox scale (Maddox and Rush, 1977), by the attending physician. Cumulative severity, i.e. the sum of scores for phlebitis, was calculated during the infusion period. Number of cannulation site changes, duration of intravenous infusions and daily weights of the infants were recorded. Weight changes were calculated as percentages of birth weight. Preterm infants were born at less than 37 weeks' gestational ages. Infants with birth weight less than 2 SD from the mean for

0 No pain around the tip of the catheter, no color, no redness, no hardening,

3+ Pain around the tip of the catheter, redness, swelling and hardening

Table 1. Modified Maddox score scale (Maddox and Rush, 1977): observation criteria for

Irritation in the site of infusion, number of cannula site changes and weight gain were chosen as primary end points. The sample size was calculated on the assumption that either glucose solution might reduce the mean number of cannula site changes from 1.5 to 1.0. With 80% power and statistical significance level below 0.05 the sample size would be 57 in each group. The dropout rate was estimated to be about 5%, and thus the goal was to recruit

*t*-test, Mann–Whitney *U*-test and analysis of variance for repeated measures were used in the statistical analysis, as appropriate. P-value less than 0.05 was regarded as statistically

During the study period, hypoglycemia was diagnosed in 465 neonates. Of these, 108 did not fulfill the inclusion criteria; 357 were eligible. The parents refused consent in 12 of these cases and in 224 cases the attending physician had no possibility to request consent because of lack of time, or lack of possibility to contact the mother. Sixty infants were allocated to the

the glucose concentration the group allocation was not possible to be blinded.

gestational age were defined as small for gestational age (SGA).

1+ Pain around the tip of the catheter and redness

The ethical committee of the hospital had approved the study.

group 20% and 61 to the group 15%. (Figure 1)

2+ Pain around the tip of the catheter, redness and swelling

vein not hard when palpated.

phlebitis.

significant.

**3. Results**

**2.1 Statistical analysis**

60 infants for both groups.

infusions can be used. In such occasions the effect of the infusion rate on the risk of phlebitis seems not have been established. Earlier surveys suggest that high infusion flow rates might even markedly increase the risk of infusion failure (Hecker 1989, Hecker, et al 1991).

The occurrence of phlebitis has been evaluated in adults in a comparison of peripheral infusions of nutrient solutions with and without 20% fat emulsion (Daly et al., 1985). Adding fat to the fluids did not protect the veins from the development of phlebitis. Infiltration was more dependent on the catheters than on the osmolarity of solutions. In keeping with this, peripheral intravenous nutrition caused phlebitis in all patients using Teflon cannulas, but in only 7% using silicone catheters. The risk of phlebitis was very low even when nutrition solutions of an osmolarity of 1250 mOsm/kg were administered via the latter catheters (Madan et al., 1992).

Glucose solutions are acid and hyperosmolar, the 15% solution pH ranging between 3.5–5.5 and osmolarity 832.5 mOsm/kg and the 20% solution 4.0 and 1110 mOsm/kg. In spite of this, the latter solution might be a better choice in the management of hypoglycemia, because the fluid administration rate of the 20% solution to reach the same glucose intake is 25% lower compared to 15% glucose solution. Thus, risk of excessive fluid load can be decreased by using 20% glucose instead of 15% glucose infusion. As far as we know no earlier studies comparing the infusions of 15 % and 20% glucose into peripheral veins of newborn infants have been done.

The purpose of our study was to evaluate, whether peripheral intravenous 20% glucose solutions are as well tolerated as 15% glucose solutions in the management of neonatal hypoglycemia.

#### **2. Patients and methods**

The study was undertaken in the neonatal unit of Tampere University Hospital (Vanhatalo and Tammela, 2010). Newborn infants with hypoglycemia for which initiation of intravenous glucose infusion was prescribed at the discretion of the attending physician, were included in the study if they fulfilled the following criteria: (1) birth weight of 2000 g or more, (2) no significant malformations diagnosed, (3) intensive care not needed, (4) written informed consent obtained from the parents. Infants in intensive care were excluded in order to minimize confounding factors, including need of vasoactive infusions and/or multiple intravenous medications.

Hypoglycemia was defined as a plasma glucose level below 2.6 mmol/L and hyperglycemia as above 7.7 mmol/L. All infants received either their own mother's or banked pooled breast milk. On-demand breast and/or bottle feeding was preferred. Breast-fed infants were weighed before and after feedings, in order to measure the ingested milk volume. The minimum cumulative amount of breast milk was 80 mL, divided by 8-10 feedings, in the first day of life. The cumulative milk volume was daily increased by 80 mL, up to 170 mL/kg/day. Increasing the daily number of oral feedings was the first treatment for hypoglycemia. Gavage feeding was used in babies, who were sucking poorly. Intravenous glucose infusion was started at the discretion of the attending physician in cases with symptomatic hypoglycemia, recurrent blood glucose levels below 2.6 mmol/L, in spite of increased oral or tube feedings, and in hypoglycemic infants, who tolerated poorly enteral feedings. The infants were randomized to receive either 20% (group 20%, 60 infants) or 15% (group 15%, 61 infants) peripheral intravenous glucose infusions at an initiation glucose intake rate of 8 mg/kg/min, i.e. 2.4 mL/kg/h in the group 20% and 3.2 mL/kg/h in the 15% group. The group allocation of each patient was written in a sealed envelope, which was opened after the written consent was received from the parents. Because infusion rates were dependent on the glucose concentration the group allocation was not possible to be blinded.

The infants' plasma glucose levels were measured every 4 h and the infusion rate reduced after each measurement by 0.5 mL/kg/h at blood glucose levels between 3.5–4 mmol/L and by 1 mL/kg/h at blood glucose levels above 4 mmol/L. The infusion was stopped when the plasma glucose level was 3.5 mmol/L or higher at an infusion rate of 2 mL/h. Plasma glucose surveillance was continued, until levels had remained normal (more than 2.9 mmoL/L) for 24 h after discontinuation of the glucose infusion. When the cannulation site had to be changed, local signs of phlebitis at the previous site were scored from 0 to 3 using a modified Maddox scale (Maddox and Rush, 1977), by the attending physician. Cumulative severity, i.e. the sum of scores for phlebitis, was calculated during the infusion period. Number of cannulation site changes, duration of intravenous infusions and daily weights of the infants were recorded. Weight changes were calculated as percentages of birth weight. Preterm infants were born at less than 37 weeks' gestational ages. Infants with birth weight less than 2 SD from the mean for gestational age were defined as small for gestational age (SGA).

0 No pain around the tip of the catheter, no color, no redness, no hardening, vein not hard when palpated.

1+ Pain around the tip of the catheter and redness

2+ Pain around the tip of the catheter, redness and swelling

3+ Pain around the tip of the catheter, redness, swelling and hardening

Table 1. Modified Maddox score scale (Maddox and Rush, 1977): observation criteria for phlebitis.

#### **2.1 Statistical analysis**

104 Hypoglycemia – Causes and Occurrences

infusions can be used. In such occasions the effect of the infusion rate on the risk of phlebitis seems not have been established. Earlier surveys suggest that high infusion flow rates might

The occurrence of phlebitis has been evaluated in adults in a comparison of peripheral infusions of nutrient solutions with and without 20% fat emulsion (Daly et al., 1985). Adding fat to the fluids did not protect the veins from the development of phlebitis. Infiltration was more dependent on the catheters than on the osmolarity of solutions. In keeping with this, peripheral intravenous nutrition caused phlebitis in all patients using Teflon cannulas, but in only 7% using silicone catheters. The risk of phlebitis was very low even when nutrition solutions of an osmolarity of 1250 mOsm/kg were administered via the

Glucose solutions are acid and hyperosmolar, the 15% solution pH ranging between 3.5–5.5 and osmolarity 832.5 mOsm/kg and the 20% solution 4.0 and 1110 mOsm/kg. In spite of this, the latter solution might be a better choice in the management of hypoglycemia, because the fluid administration rate of the 20% solution to reach the same glucose intake is 25% lower compared to 15% glucose solution. Thus, risk of excessive fluid load can be decreased by using 20% glucose instead of 15% glucose infusion. As far as we know no earlier studies comparing the infusions of 15 % and 20% glucose into peripheral veins of

The purpose of our study was to evaluate, whether peripheral intravenous 20% glucose solutions are as well tolerated as 15% glucose solutions in the management of neonatal

The study was undertaken in the neonatal unit of Tampere University Hospital (Vanhatalo and Tammela, 2010). Newborn infants with hypoglycemia for which initiation of intravenous glucose infusion was prescribed at the discretion of the attending physician, were included in the study if they fulfilled the following criteria: (1) birth weight of 2000 g or more, (2) no significant malformations diagnosed, (3) intensive care not needed, (4) written informed consent obtained from the parents. Infants in intensive care were excluded in order to minimize confounding factors, including need of vasoactive infusions and/or

Hypoglycemia was defined as a plasma glucose level below 2.6 mmol/L and hyperglycemia as above 7.7 mmol/L. All infants received either their own mother's or banked pooled breast milk. On-demand breast and/or bottle feeding was preferred. Breast-fed infants were weighed before and after feedings, in order to measure the ingested milk volume. The minimum cumulative amount of breast milk was 80 mL, divided by 8-10 feedings, in the first day of life. The cumulative milk volume was daily increased by 80 mL, up to 170 mL/kg/day. Increasing the daily number of oral feedings was the first treatment for hypoglycemia. Gavage feeding was used in babies, who were sucking poorly. Intravenous glucose infusion was started at the discretion of the attending physician in cases with symptomatic hypoglycemia, recurrent blood glucose levels below 2.6 mmol/L, in spite of increased oral or tube feedings, and in hypoglycemic infants, who tolerated poorly enteral feedings. The infants were randomized to receive either 20% (group 20%, 60 infants) or 15% (group 15%, 61 infants) peripheral intravenous glucose infusions at an initiation glucose intake rate of 8 mg/kg/min, i.e. 2.4 mL/kg/h in the group 20% and 3.2 mL/kg/h in the 15% group.

even markedly increase the risk of infusion failure (Hecker 1989, Hecker, et al 1991).

latter catheters (Madan et al., 1992).

newborn infants have been done.

**2. Patients and methods**

multiple intravenous medications.

hypoglycemia.

Irritation in the site of infusion, number of cannula site changes and weight gain were chosen as primary end points. The sample size was calculated on the assumption that either glucose solution might reduce the mean number of cannula site changes from 1.5 to 1.0. With 80% power and statistical significance level below 0.05 the sample size would be 57 in each group. The dropout rate was estimated to be about 5%, and thus the goal was to recruit 60 infants for both groups.

*t*-test, Mann–Whitney *U*-test and analysis of variance for repeated measures were used in the statistical analysis, as appropriate. P-value less than 0.05 was regarded as statistically significant.

The ethical committee of the hospital had approved the study.

### **3. Results**

During the study period, hypoglycemia was diagnosed in 465 neonates. Of these, 108 did not fulfill the inclusion criteria; 357 were eligible. The parents refused consent in 12 of these cases and in 224 cases the attending physician had no possibility to request consent because of lack of time, or lack of possibility to contact the mother. Sixty infants were allocated to the group 20% and 61 to the group 15%. (Figure 1)

Glucose Infusions into Peripheral Veins in Neonates with Hypoglycemia 107

treatment due to suspected or confirmed infection was more common in the group 20%, but the differences did not reach statistical significance. About half of the cases in both groups were infants of diabetic mothers (mean 30 (SD 49) % vs. 30 (SD 50) %). In the group 20%, 25 mothers and in the group 15%, 21 mothers had gestational diabetes, five versus nine mothers had type 1diabetes and seven versus 12 mothers were on insulin medication in the 20 and 15% groups, respectively, NS. Three mothers had pre-eclampsia in the group 20% and five in the group 15%. Ten mothers had hypertension in the group 20% and six in the group 15%. Ten mothers had signs of chorioamnionitis at delivery in the group 20% and six

The concentrations of electrolytes in the glucose solutions, adjusted according to the plasma sodium and potassium levels, were similar in the two groups: the mean (SD) sodium concentrations being 38 (15) mmol/L versus 39 (12) mmol/L and potassium concentrations 12 mmol/L versus 13 mmol/L, respectively. Seven (12%) infants in the group 20% and 11 (18%) in the group 15% also received antibiotic treatment, the mean durations of antibiotic

The mean (SD) duration of cannulation was in the group 20% 4.2 (1.4) days and in the group 15% 3.9 (1.3) days, NS. The number of cannulation site changes were median 1 (range 0–5) in the group 20% and 1 (range 0–6) in the group 15%, respectively, NS. In the 20% group 35 infants (59%) and in the 15% group 36 (60%) had some signs of phlebitis, NS. The cumulative severity score for phlebitis was low in both groups, in the 20% glucose group a

When the infants, who received antibiotics, were omitted, in infants receiving only intravenous glucose infusions, the mean (SD) duration of cannulation was in the group 20% 4.0 (1.3) days and in the group 15% 4.0 (1.3) days, NS. The number of cannulation site changes were median 1 (range 0–6), and 1 (range 0–5), respectively, NS. In the 20% group 31 (63%) and in the 15% group 33 infants (61%) had some signs of phlebitis, NS. The cumulative severity score for phlebitis was in the 20% group median 1 (range 0–8) and in the

Average plasma glucose levels were similar in both groups in the 20% group 4.6 (0.41) and in the 15% group 4.5 (0.37) mmol/L. High plasma glucose levels occurred in nine cases in the 20% glucose group and in 11 in the 15% group, and low levels in 37 versus 43 infants in

Weight as a function of infusion time and relative weight changes in the two groups were

A recruitment bias is possible in this cohort in that the attending physician was not able to contact some mothers to obtain informed consent. A significant number of eligible infants were thus left out. This circumstance can be explained by the fact that a substantial proportion of hypoglycemia cases are admitted outside office hours, during which time the paediatricians on call are often too busy, and during the night reluctant to disturb the parents' sleep in order to recruit their baby for the study. It is also not possible to postpone

Maternal diabetes mellitus is one of the most important risk factors for neonatal hypoglycemia, and its severity might affect the need and duration of intravenous glucose infusion of the infants. Both small and large birth weight for gestational age might also be

the start of intravenous glucose infusion for long in hypoglycemic patients.

in the group 15%, respectively.

treatment being 6.0 (0.6) versus 5.2 (1.3) days, NS.

15% glucose group 1.5 (range 0–8), NS.

the 20% and 15% groups, respectively, NS.

similar (Figure 2), NS.

**4. Discussion**

median of 1 (range 0–7) and in the 15% group 1 (range 0–8), NS.

#### Fig. 1. Allocation of the study groups

The infants in the 20% and 15% groups were born at similar (mean (SD)) weeks' gestation (group 20% 39 (1.5) weeks vs. group 15% 39 (1.3) weeks) and birth weights (3605 (593) g vs. 3486 (626) g, respectively). Female/male ratios did not differ (23/38 vs. 24/36).

Similar percentages of infants in both groups had been delivered via caesarean section, were SGA or had birth weights >4500 g (Table 2). Few cases in either group were born from twin pregnancies and asphyxia was rare. Prematurity, need for phototherapy and antibiotic

The differences between the groups were not statistically significant

Table 2. Clinical characteristics of the infants in the study groups

treatment due to suspected or confirmed infection was more common in the group 20%, but the differences did not reach statistical significance. About half of the cases in both groups were infants of diabetic mothers (mean 30 (SD 49) % vs. 30 (SD 50) %). In the group 20%, 25 mothers and in the group 15%, 21 mothers had gestational diabetes, five versus nine mothers had type 1diabetes and seven versus 12 mothers were on insulin medication in the 20 and 15% groups, respectively, NS. Three mothers had pre-eclampsia in the group 20% and five in the group 15%. Ten mothers had hypertension in the group 20% and six in the group 15%. Ten mothers had signs of chorioamnionitis at delivery in the group 20% and six in the group 15%, respectively.

The concentrations of electrolytes in the glucose solutions, adjusted according to the plasma sodium and potassium levels, were similar in the two groups: the mean (SD) sodium concentrations being 38 (15) mmol/L versus 39 (12) mmol/L and potassium concentrations 12 mmol/L versus 13 mmol/L, respectively. Seven (12%) infants in the group 20% and 11 (18%) in the group 15% also received antibiotic treatment, the mean durations of antibiotic treatment being 6.0 (0.6) versus 5.2 (1.3) days, NS.

The mean (SD) duration of cannulation was in the group 20% 4.2 (1.4) days and in the group 15% 3.9 (1.3) days, NS. The number of cannulation site changes were median 1 (range 0–5) in the group 20% and 1 (range 0–6) in the group 15%, respectively, NS. In the 20% group 35 infants (59%) and in the 15% group 36 (60%) had some signs of phlebitis, NS. The cumulative severity score for phlebitis was low in both groups, in the 20% glucose group a median of 1 (range 0–7) and in the 15% group 1 (range 0–8), NS.

When the infants, who received antibiotics, were omitted, in infants receiving only intravenous glucose infusions, the mean (SD) duration of cannulation was in the group 20% 4.0 (1.3) days and in the group 15% 4.0 (1.3) days, NS. The number of cannulation site changes were median 1 (range 0–6), and 1 (range 0–5), respectively, NS. In the 20% group 31 (63%) and in the 15% group 33 infants (61%) had some signs of phlebitis, NS. The cumulative severity score for phlebitis was in the 20% group median 1 (range 0–8) and in the 15% glucose group 1.5 (range 0–8), NS.

Average plasma glucose levels were similar in both groups in the 20% group 4.6 (0.41) and in the 15% group 4.5 (0.37) mmol/L. High plasma glucose levels occurred in nine cases in the 20% glucose group and in 11 in the 15% group, and low levels in 37 versus 43 infants in the 20% and 15% groups, respectively, NS.

Weight as a function of infusion time and relative weight changes in the two groups were similar (Figure 2), NS.

#### **4. Discussion**

106 Hypoglycemia – Causes and Occurrences

The infants in the 20% and 15% groups were born at similar (mean (SD)) weeks' gestation (group 20% 39 (1.5) weeks vs. group 15% 39 (1.3) weeks) and birth weights (3605 (593) g vs.

Similar percentages of infants in both groups had been delivered via caesarean section, were SGA or had birth weights >4500 g (Table 2). Few cases in either group were born from twin pregnancies and asphyxia was rare. Prematurity, need for phototherapy and antibiotic

> **20% Glucose group 15% Glucose group N (%) N (%)**

randomized 121

20 % group 60

15% group 61

3486 (626) g, respectively). Female/male ratios did not differ (23/38 vs. 24/36).

Refused 12 Participants

Consent not requested 224

Cesarean section 7 (12) 6 (11) Small for gestational age (SGA) 0 (0) 2 (5) Birth weight > 4500 g 2 (3) 3 (5) Female/male 24/36 23/38 Twins 3 (5) 2 (3) Premature 8 (13) 4 (7) Five minute Apgar score < 7 2 (3) 4 (7) Phototherapy 20 (33) 14 (23) Intravenous antibiotics 12 (20) 6 (11)

The differences between the groups were not statistically significant Table 2. Clinical characteristics of the infants in the study groups

Fig. 1. Allocation of the study groups

465 hypoglycemic neonates

Not eligible 108 Eligible 357

A recruitment bias is possible in this cohort in that the attending physician was not able to contact some mothers to obtain informed consent. A significant number of eligible infants were thus left out. This circumstance can be explained by the fact that a substantial proportion of hypoglycemia cases are admitted outside office hours, during which time the paediatricians on call are often too busy, and during the night reluctant to disturb the parents' sleep in order to recruit their baby for the study. It is also not possible to postpone the start of intravenous glucose infusion for long in hypoglycemic patients.

Maternal diabetes mellitus is one of the most important risk factors for neonatal hypoglycemia, and its severity might affect the need and duration of intravenous glucose infusion of the infants. Both small and large birth weight for gestational age might also be

Glucose Infusions into Peripheral Veins in Neonates with Hypoglycemia 109

cannulation changes in the cases on both groups is in accordance with the previous data. Thus, the duration of cannulation, number of cannulation changes and phlebitis severity scores were similar in both groups. One can assume, that the safety of peripheral 20 or 15% glucose intravenous infusions is similar also in neonates, who need intravenous glucose infusions for other reasons than hypoglycemia, including short-term parenteral nutrition. The occurrence of phlebitis has been evaluated in adults in a comparison of peripheral infusions of nutrient solutions with and without 20% fat emulsion (Daly JM et al., 1985). Adding fat to the fluids did not protect the veins from the development of phlebitis. Infiltration was more dependent on the catheters than on the osmolarity of solutions. In keeping with this, peripheral intravenous nutrition caused phlebitis in all patients using Teflon cannulas, but in only 7% using silicone catheters. The risk of phlebitis was very low even when nutrition solutions of an osmolarity of 1250 mOsm/kg were administered via the latter catheters (Madan M et al., 1992). In our study, the same peripheral catheters were used in both groups and therefore the role of catheter type in the development of phlebitis cannot

Although infants in the 20% glucose group received 33% less fluids than those in the 15% group, no differences in weight changes were seen. Our infants were all quite healthy, having no or mild neonatal problems in addition to hypoglycemia and would thus seem to tolerate excess amounts of fluids well. Our study was not powered to establish, whether less fluid intake would be beneficial by decreasing risk of respiratory problems and need of oxygen supplementation in the 20% glucose group compared to the 15% glucose group. In patients who do not tolerate fluids normally, as in cases of birth asphyxia, renal failure, bronchopulmonary dysplasia or inappropriate antidiuretic hormone excretion, reduction of fluid intake by using 20% instead of 15% glucose might have beneficial effect on the

Intravenous 20% glucose solutions can be infused into peripheral veins as safely as 15% glucose solutions. The risks of excess fluid intake, in addition to oral feeding, need to be

Daly JM, Masser RN, Hansen L, Canham JE. Peripheral vein infusion of dextrose/amino

Hecker JF, Duffy BJ, Fong T& Wyer M (1991) Failure of intravenous infusion in neonates. *J Paediatr Child Health* Vol. 27. No. 4. (June 1991), pp 175-179, ISSN 1034-4810 Kien CL. Carbohydrates. In: Tsang RC, Lucas A, UayR, ZlotkinS, editors. *Nutritional needs of*

Leake RD, Zakauddin S, Trygstad CW, Fu P, Oh W (1976) The effects of large volume

*care* Vol 17, No. 4 November 1989), pp 433-449, ISSN 0310-057X

acid solutions ± 20% fat emulsion. *J Parent Ent Nutr* 1985; **9**: 296. ecker JF (1989) Failure of intravenous infusions from extravasation and phlebitis. *Anaesth Intensive*

*the preterm infant: nutritional*. New York : Caduceus Medical Publishers Inc, 1993:

intravenous fluid infusion on neonatal renal function. J Pediatr Vol 89, No. 6 (June

established in further studies in infants with neonatal hypoglycemia.

be established here.

outcome of the patient.

**5. Conclusion**

**6. References**

47–63.

1976), pp 968-972, ISSN 0022-3476

Fig. 2. Relative change in weight (% from birth weight) during intravenous glucose infusion. Circles indicate the 15% glucose and squares the 20% glucose group. X axis: weight changes. Y axis: time (days).

associated with a prolonged need of intravenous glucose infusion. The groups were, however, quite well matched for the percentages of mothers having gestational diabetes, type 1diabetes, for receiving insulin medication, and percentages of either SGA or LGA infants. Breast milk feeding is a cornerstone in the prevention and management of neonatal hypoglycemia, and weaning from intravenous glucose infusion is not possible without a successful feeding. The same feeding protocol was used in both groups.

Concomitant use of intravenous antibiotics during intravenous glucose infusion increases obviously the risk of phlebitis, and is therefore a confounding factor in the comparison between 15% and 20% glucose groups. The percentage of infants receiving antibiotics was somewhat, although not significantly higher in the 20% group. The higher osmolarity of the 20% glucose solution was, however, not associated with an increased rate or severity of phlebitis in our infants. In addition, omitting the antibiotic-treated cases did not change the result. The electrolyte concentrations in the 15 % and 20 % glucose infusion fluids were similar. As intravenous glucose was administered at the same rate (mg/kg/min) in both study groups, the 15% glucose group received fluids at a 33% higher rate than the 20% glucose group. The differences in fluid infusion rates might even have balanced the local effect of different glucose concentrations on the vessel wall at the infusion site.

The clinical classification of phlebitis also involves risk of bias, as observation and classification is subjective. The observers rating the severity of the phlebitis were not aware of the glucose concentration used in each case. Accidental detachment of intravenous lines occurs only rarely and the most common reason for a cannulation site change is local irritation and swelling at the infusion site. The number of cannulation site changes would thus seem to be a fairly objective measure of extravasation of fluids. According to earlier work, extravasation of peripheral fluid infusions occurs by 36 h in more than half of the patients (Möller, et al., 1996, Hecker et al.,1991). In our patients the mean duration of cannulation was about four days in both groups, suggesting that the median number of cannulation changes in the cases on both groups is in accordance with the previous data. Thus, the duration of cannulation, number of cannulation changes and phlebitis severity scores were similar in both groups. One can assume, that the safety of peripheral 20 or 15% glucose intravenous infusions is similar also in neonates, who need intravenous glucose infusions for other reasons than hypoglycemia, including short-term parenteral nutrition.

The occurrence of phlebitis has been evaluated in adults in a comparison of peripheral infusions of nutrient solutions with and without 20% fat emulsion (Daly JM et al., 1985). Adding fat to the fluids did not protect the veins from the development of phlebitis. Infiltration was more dependent on the catheters than on the osmolarity of solutions. In keeping with this, peripheral intravenous nutrition caused phlebitis in all patients using Teflon cannulas, but in only 7% using silicone catheters. The risk of phlebitis was very low even when nutrition solutions of an osmolarity of 1250 mOsm/kg were administered via the latter catheters (Madan M et al., 1992). In our study, the same peripheral catheters were used in both groups and therefore the role of catheter type in the development of phlebitis cannot be established here.

Although infants in the 20% glucose group received 33% less fluids than those in the 15% group, no differences in weight changes were seen. Our infants were all quite healthy, having no or mild neonatal problems in addition to hypoglycemia and would thus seem to tolerate excess amounts of fluids well. Our study was not powered to establish, whether less fluid intake would be beneficial by decreasing risk of respiratory problems and need of oxygen supplementation in the 20% glucose group compared to the 15% glucose group. In patients who do not tolerate fluids normally, as in cases of birth asphyxia, renal failure, bronchopulmonary dysplasia or inappropriate antidiuretic hormone excretion, reduction of fluid intake by using 20% instead of 15% glucose might have beneficial effect on the outcome of the patient.

#### **5. Conclusion**

108 Hypoglycemia – Causes and Occurrences

1234

Fig. 2. Relative change in weight (% from birth weight) during intravenous glucose infusion. Circles indicate the 15% glucose and squares the 20% glucose group. X axis: weight changes.

associated with a prolonged need of intravenous glucose infusion. The groups were, however, quite well matched for the percentages of mothers having gestational diabetes, type 1diabetes, for receiving insulin medication, and percentages of either SGA or LGA infants. Breast milk feeding is a cornerstone in the prevention and management of neonatal hypoglycemia, and weaning from intravenous glucose infusion is not possible without a

Concomitant use of intravenous antibiotics during intravenous glucose infusion increases obviously the risk of phlebitis, and is therefore a confounding factor in the comparison between 15% and 20% glucose groups. The percentage of infants receiving antibiotics was somewhat, although not significantly higher in the 20% group. The higher osmolarity of the 20% glucose solution was, however, not associated with an increased rate or severity of phlebitis in our infants. In addition, omitting the antibiotic-treated cases did not change the result. The electrolyte concentrations in the 15 % and 20 % glucose infusion fluids were similar. As intravenous glucose was administered at the same rate (mg/kg/min) in both study groups, the 15% glucose group received fluids at a 33% higher rate than the 20% glucose group. The differences in fluid infusion rates might even have balanced the local

The clinical classification of phlebitis also involves risk of bias, as observation and classification is subjective. The observers rating the severity of the phlebitis were not aware of the glucose concentration used in each case. Accidental detachment of intravenous lines occurs only rarely and the most common reason for a cannulation site change is local irritation and swelling at the infusion site. The number of cannulation site changes would thus seem to be a fairly objective measure of extravasation of fluids. According to earlier work, extravasation of peripheral fluid infusions occurs by 36 h in more than half of the patients (Möller, et al., 1996, Hecker et al.,1991). In our patients the mean duration of cannulation was about four days in both groups, suggesting that the median number of

successful feeding. The same feeding protocol was used in both groups.

effect of different glucose concentrations on the vessel wall at the infusion site.

**15% glucose**

Y axis: time (days).

0

**20% glucose**

Intravenous 20% glucose solutions can be infused into peripheral veins as safely as 15% glucose solutions. The risks of excess fluid intake, in addition to oral feeding, need to be established in further studies in infants with neonatal hypoglycemia.

#### **6. References**

**Part 3**

**Section C**

**Part 3**

**Section C**

110 Hypoglycemia – Causes and Occurrences

Kuwahara T, Asanami S, Tamura T, Kaneda S. Effects of pH and osmolality on phlebitic

Kuwahara T, Asanami S, Kubo S. Experimental infusion phlebitis: tolerance osmolality of peripheral venous endothelial cells. *Nutrition* 1998; 14: 496–501, ISSN 0899-9007 Madan M, Alexander DJ, McMahon MJ. Influence of catheter type on occurrence of

Maddox RR, Rush DR. Double-blind study to investigate methods to prevent cephalotininduced phlebitis. *Am J Hosp Pharm* 1977; 34: 29–34, ISSN 0002-9289

Möller JC, Reiss I, Schaible Th. Vascular access in neonates and infants – indications, routes, techniques and devices, complications. *Intensive Care World* 1995; 12: 48–53. Vanhatalo T, Tammela O. Glucose infusions into peripheral veins in the management of

Vuohelainen T, Ojala R, Virtanen A, Laatta J, Mörsky P, Uotila J and Tammela O (2002).

*Pediatr Res* 2007, Vol 62, No 1 (Jul 2007), pp. 106-110, ISSN 0031-3998 Vuohelainen T, Ojala R, Virtanen A, Holm P and Tammela O (2001). Predictors of delayed

23: 77–85, ISSN 0388-1350

ISSN 0140-6736

0803-5253

ISSN 0803-5253

potential of infusion solutions for peripheral parenteral nutrition. *J Toxicol Sci* 1998;

thrombophlebitis during peripheral intravenous nutrition. *Lancet* 1992; 339: 101–3,

neonatal hypoglycemia--20% instead of 15%?. *Acta Pædiatr* 2010;99:350-353, ISSN

Predictors of AVP and TSH levels and the timing of first voiding in the newborn*.*

first voiding in newborn. *Acta Paediatr* 2008, Vol 97, No 7 (July 2008), pp. 904-908,

**8**

*United States*

**Drug-Induced Hypoglycemia**

*Auburn University, Harrison School of Pharmacy*

Although it is noted throughout the literature that adverse effects occur, one review of safety reporting determined clinical trials only report adverse effects between 29% (laboratory adverse effects) and 39% (clinical adverse effects) (Ioannidis, et al, 2001). It is important to keep these numbers in mind when looking at the number of drug-induced hypoglycemia cases. Seltzer's review of the literature from 1940 to 1989 reveals 1418 documented cases of drug-induced hypoglycemia. Based on estimates of the lack of adverse effect reporting, it is unlikely that these cases were the only incidents of drug-induced

It is also reasonable to look at estimates of adverse drug effects (ADEs) in hospitalized patients. Such estimates indicate ADEs may account for between 3 and 5% of all hospital admissions (Pandit et al, 1993). In a 2006 study it was determined approximately 22% of admissions attributed to ADEs were due to hypoglycemia at a university hospital versus 23% at a community hospital (Kilbridge et al, 2006). These admissions were related to an overall admission rate attributed to ADEs of 4.4% at the university hospital and 6.2% at a community hospital (Kilbridge et al, 2006). In addition there are estimates that as many as 30% of hospitalized patients experience an ADE while in the hospital (Pandit et al, 1993). Estimates of 3 – 4.5 billion dollars, which is now outdated, just begin to attribute a cost to treating ADEs. However, the cost is probably grossly underestimated since the actual number of ADEs reported is underestimated (Pandit et al, 1993). Not only is the cost of managing an ADEs a significant issue but the risk of mortality must be considered as well. Mortality has been estimated to occur in as many as 140,000 patients each year (Pandit et al, 1993). One study looking at death due to drug-induced hypoglycemia determined a 1.3% mortality rate

The incidence and impact of drug-induced hypoglycemia should be contrasted with the incidence and impact of hypoglycemia in patients with diabetes mellitus (DM) – type 1 or type 2. For patients with type 1 DM, it is estimated that hypoglycemia, by the numbers (blood glucose less than 50 – 60 mg/dL), occurs 1 in 10 times when patients check their blood glucose (Cryer et al, 2003). While the number of asymptomatic hypoglycemia episodes is undocumented, it is estimated that patients with type 1 DM experience "an average of 2 symptomatic hypoglycemic episodes per week.and an episode of severe, at least temporarily disabling hypoglycaemia once a year" (Cryer et al, 2003). The incidence of hypoglycemia in patients with type 2 DM is more challenging. When comparing the incidence of severe hypoglycemia in patients with type 1 DM versus patients with type 2 DM being treated with insulin, estimates are anywhere from 10% to equal incidence of hypoglycemia (Cryer et al, 2003). Other studies that have tried to quantify the incidence of

hypoglycemia that occurred during this time (Seltzer, 1989).

**1. Introduction**

(Juurlink et al, 2003).

Kristen Helms and Kristi Kelley

## **Drug-Induced Hypoglycemia**

Kristen Helms and Kristi Kelley

*Auburn University, Harrison School of Pharmacy United States*

#### **1. Introduction**

Although it is noted throughout the literature that adverse effects occur, one review of safety reporting determined clinical trials only report adverse effects between 29% (laboratory adverse effects) and 39% (clinical adverse effects) (Ioannidis, et al, 2001). It is important to keep these numbers in mind when looking at the number of drug-induced hypoglycemia cases. Seltzer's review of the literature from 1940 to 1989 reveals 1418 documented cases of drug-induced hypoglycemia. Based on estimates of the lack of adverse effect reporting, it is unlikely that these cases were the only incidents of drug-induced hypoglycemia that occurred during this time (Seltzer, 1989).

It is also reasonable to look at estimates of adverse drug effects (ADEs) in hospitalized patients. Such estimates indicate ADEs may account for between 3 and 5% of all hospital admissions (Pandit et al, 1993). In a 2006 study it was determined approximately 22% of admissions attributed to ADEs were due to hypoglycemia at a university hospital versus 23% at a community hospital (Kilbridge et al, 2006). These admissions were related to an overall admission rate attributed to ADEs of 4.4% at the university hospital and 6.2% at a community hospital (Kilbridge et al, 2006). In addition there are estimates that as many as 30% of hospitalized patients experience an ADE while in the hospital (Pandit et al, 1993). Estimates of 3 – 4.5 billion dollars, which is now outdated, just begin to attribute a cost to treating ADEs. However, the cost is probably grossly underestimated since the actual number of ADEs reported is underestimated (Pandit et al, 1993). Not only is the cost of managing an ADEs a significant issue but the risk of mortality must be considered as well. Mortality has been estimated to occur in as many as 140,000 patients each year (Pandit et al, 1993). One study looking at death due to drug-induced hypoglycemia determined a 1.3% mortality rate (Juurlink et al, 2003).

The incidence and impact of drug-induced hypoglycemia should be contrasted with the incidence and impact of hypoglycemia in patients with diabetes mellitus (DM) – type 1 or type 2. For patients with type 1 DM, it is estimated that hypoglycemia, by the numbers (blood glucose less than 50 – 60 mg/dL), occurs 1 in 10 times when patients check their blood glucose (Cryer et al, 2003). While the number of asymptomatic hypoglycemia episodes is undocumented, it is estimated that patients with type 1 DM experience "an average of 2 symptomatic hypoglycemic episodes per week.and an episode of severe, at least temporarily disabling hypoglycaemia once a year" (Cryer et al, 2003). The incidence of hypoglycemia in patients with type 2 DM is more challenging. When comparing the incidence of severe hypoglycemia in patients with type 1 DM versus patients with type 2 DM being treated with insulin, estimates are anywhere from 10% to equal incidence of hypoglycemia (Cryer et al, 2003). Other studies that have tried to quantify the incidence of

Drug-Induced Hypoglycemia 115

 Epinephrine release Growth hormone release

Cortisol release

Cognitive decline

Seizures

**Examples of Psychological Morbidity Associated with Hypoglycemia**

Fear of experiencing hypoglycemia

Guilt related to being fearful of experiencing hypoglycaemia

Anxiet

overall happiness

Blood glucose level Classification Physiologic response 70 mg/dl (3.9 mmol/l) Hypoglycemia Glucagon release

54 mg/dl (3 mmol/l) Symptomatic hypoglycemia Autonomic symptoms

It is important to note that monitoring blood glucose levels is the best way to monitor hypoglycemia since hemoglobin A1C (A1C) does not adequately depict hypoglycemia given that A1C provides a measure of average control of blood glucose over the past 2 to 3 months

In one technical review of hypoglycemia in patients with diabetes, it was noted that hypoglycemia resulted in "physical morbidity" as evidenced in the physical symptoms and even neurologic impairment patients may experience as well as "psychological morbidity" which were differences in moods and outlook as a result of experiencing hypoglycemia (Cryer PE et al, 2003). Specific manifestations of physical and psychological morbidity are detailed in Table 3. When thinking of these symptoms of hypoglycemia, it should be recognized that they can make patients feel uncomfortable physically as well as socially since experiencing these symptoms may result in patients receiving unwanted attention. It is important to consider that hypoglycemia affects patients both physically, psychologically, and can have a significant impact on a patient's overall sense of well-being. Although the same evidence does not exist for patients that experience drug-induced hypoglycemia, it could be argued that the toll is equally as hard on these individuals and therefore,

brain function (neuroglucopenia)

18 mg/dl (1 mmol/l) Severe neuroglucopenia Coma

emphasizes the importance of avoiding drug-induced hypoglycemia.

Table 3. Physical and psychological morbidity associated with hypoglycemia.

36 mg/dl (2 mmol/l) Hypoglycemia affecting

Table 2. Physiologic response based on blood glucose level

Adapted from White, 2007

(American Diabetes Association, 2011).

**Examples of Physical Morbidity Associated with Hypoglycemia**

Physical symptoms – anxiety, hunger, palpitations, sweating, hunger

Neurologic impairment – changes in behavior, decline in cognitive function,

Adapted from Cryer PE et al, 2003

seizures, coma

hypoglycemia in type 2 patients have varied from an overall incidence of 20% in patients taking oral agents to 0.5% episodes of severe hypoglycemia in patients using insulin (Jennings AM et al, 1989 & Miller CD et al, 2001). Unfortunately, as with drug-induced hypoglycemia, hypoglycemia may result in death. One estimate of the rate of death from hypoglycemia is 2 to 4% of patients with type 1 DM, but, as with the incidence of hypoglycemia, there is not a reliable estimate of death attributed to hypoglycemia in patients with type 2 DM (Cryer et al, 2003). However, a 1999 review of cases of hypoglycemic coma provides some perspective on potential morbidity and mortality. In this study, out of 102 reported cases, 5 patients died. (Ben-Ami et al, 1999).

These statistics emphasize the importance of recognizing and treating hypoglycemia as well as ADEs when they occur. The numbers also serve as a reminder to all healthcare providers of their responsibility in the prevention of ADEs, especially drug-induced ADEs. However, in order to prevent ADEs, one must know what patients are at risk for development of an ADE. The risk for drug-induced hypoglycemia, the mechanism of potentially causative agents as well as management and prevention are discussed below in effort to make healthcare providers aware of this potential ADE and how to avoid it.

#### **2. Definition of hypoglycemia**

Before determining if a patient is experiencing drug-induced hypoglycemia, the definition of hypoglycemia should be established. Since all patients respond to blood glucose concentrations differently, it is challenging to establish a blood glucose at which every patient will experience symptoms. However, it is widely accepted that most patients will begin to experience symptoms when their blood glucose level is less than 3.3 mmol/l (60 mg/dL). The symptoms patients commonly experience are listed in Table 1 below and can be manifestations of the response by the autonomic nervous system as well as the brain's response to being deprived of glucose (Cryer et al, 2003, White, 2007). Physiologic responses with escalating hypoglycemia are shown in Table 2. Severe episodes of hypoglycemia may be characterized by loss of consciousness and/or seizures and, in instances of sustained hypoglycemia, may result in brain damage or death (Cryer et al, 2003). The blood glucose level at which a patient experiences symptoms of hypoglycemia can be influenced by other factors such as: the frequency of hypoglycemic episodes, which may result in hypoglycemic unawareness; frequent hyperglycemia episodes, and increased caffeine intake (Cryer et al, 1999).

Adapted from Cryer et al, 2003 and White, 2007

Table 1. Common symptoms of hypoglycemia

hypoglycemia in type 2 patients have varied from an overall incidence of 20% in patients taking oral agents to 0.5% episodes of severe hypoglycemia in patients using insulin (Jennings AM et al, 1989 & Miller CD et al, 2001). Unfortunately, as with drug-induced hypoglycemia, hypoglycemia may result in death. One estimate of the rate of death from hypoglycemia is 2 to 4% of patients with type 1 DM, but, as with the incidence of hypoglycemia, there is not a reliable estimate of death attributed to hypoglycemia in patients with type 2 DM (Cryer et al, 2003). However, a 1999 review of cases of hypoglycemic coma provides some perspective on potential morbidity and mortality. In this

These statistics emphasize the importance of recognizing and treating hypoglycemia as well as ADEs when they occur. The numbers also serve as a reminder to all healthcare providers of their responsibility in the prevention of ADEs, especially drug-induced ADEs. However, in order to prevent ADEs, one must know what patients are at risk for development of an ADE. The risk for drug-induced hypoglycemia, the mechanism of potentially causative agents as well as management and prevention are discussed below in effort to make

Before determining if a patient is experiencing drug-induced hypoglycemia, the definition of hypoglycemia should be established. Since all patients respond to blood glucose concentrations differently, it is challenging to establish a blood glucose at which every patient will experience symptoms. However, it is widely accepted that most patients will begin to experience symptoms when their blood glucose level is less than 3.3 mmol/l (60 mg/dL). The symptoms patients commonly experience are listed in Table 1 below and can be manifestations of the response by the autonomic nervous system as well as the brain's response to being deprived of glucose (Cryer et al, 2003, White, 2007). Physiologic responses with escalating hypoglycemia are shown in Table 2. Severe episodes of hypoglycemia may be characterized by loss of consciousness and/or seizures and, in instances of sustained hypoglycemia, may result in brain damage or death (Cryer et al, 2003). The blood glucose level at which a patient experiences symptoms of hypoglycemia can be influenced by other factors such as: the frequency of hypoglycemic episodes, which may result in hypoglycemic unawareness;

frequent hyperglycemia episodes, and increased caffeine intake (Cryer et al, 1999).

Hunger Changes in behavior – irritability is often noted Pallor

**Hypoglycemia**

Difficulty speaking

Loss of consciousness

Shaky/trembling Confusion/difficulty thinking

Fatigue

seizures Warmth Weakness

**Neuroglycopenic Symptoms of**

Anxiety/arousal Blurry vision Increased systolic

**Physical Signs of Hypoglycemia**

blood pressure

Sweating

Tachycardia

study, out of 102 reported cases, 5 patients died. (Ben-Ami et al, 1999).

healthcare providers aware of this potential ADE and how to avoid it.

**2. Definition of hypoglycemia**

**Neurogenic Symptoms of**

Parethesias Dizziness Sweating Emotional lability

Adapted from Cryer et al, 2003 and White, 2007 Table 1. Common symptoms of hypoglycemia

**Hypoglycemia**

Adapted from White, 2007

Table 2. Physiologic response based on blood glucose level

It is important to note that monitoring blood glucose levels is the best way to monitor hypoglycemia since hemoglobin A1C (A1C) does not adequately depict hypoglycemia given that A1C provides a measure of average control of blood glucose over the past 2 to 3 months (American Diabetes Association, 2011).

In one technical review of hypoglycemia in patients with diabetes, it was noted that hypoglycemia resulted in "physical morbidity" as evidenced in the physical symptoms and even neurologic impairment patients may experience as well as "psychological morbidity" which were differences in moods and outlook as a result of experiencing hypoglycemia (Cryer PE et al, 2003). Specific manifestations of physical and psychological morbidity are detailed in Table 3. When thinking of these symptoms of hypoglycemia, it should be recognized that they can make patients feel uncomfortable physically as well as socially since experiencing these symptoms may result in patients receiving unwanted attention. It is important to consider that hypoglycemia affects patients both physically, psychologically, and can have a significant impact on a patient's overall sense of well-being. Although the same evidence does not exist for patients that experience drug-induced hypoglycemia, it could be argued that the toll is equally as hard on these individuals and therefore, emphasizes the importance of avoiding drug-induced hypoglycemia.

Adapted from Cryer PE et al, 2003

Table 3. Physical and psychological morbidity associated with hypoglycemia.

Drug-Induced Hypoglycemia 117

The processes above are all regulated by glucoregulatory hormones. The hormones, their site of origin, and specific gluco-regulatory actions are listed in table 5. In addition to those listed, blood glucose levels are affected by epinephrine, cortisol, and growth hormones

Insulin Beta (β)-cells of the pancreas Induces uptake of glucose by cells

Amylin Β-cells of the pancreas Slows gastric emptying

Inhibits glucagon secretion post-

Enhances protein and fat synthesis Stimulates glycogenesis in the liver

Stimulates hepatic glycogenolysis, hepatic gluconeogenesis, and

Inhibits glucagon secretion post-

Stimulates glucose-dependent (prandial) insulin secretion Inhibits glucagon secretion post-

prandially

prandially

prandially

prandially

L-cells of the intestine Slows gastric emptying

L-cells of the intestine Stimulates glucose-dependent

Insulin and glucagon play large roles in the overall regulation of blood glucose (Figure 1). Increases in serum blood glucose stimulate insulin release from the pancreas. The amount of insulin released is dependent on the level of blood glucose. Insulin is not released until blood glucose levels reach 3.3 mmol/l (59.4 mg/dl). Insulin acts to both decrease existing glucose in the blood and to decrease production of further glucose. Insulin binds to receptors on fat, muscle, and liver cells to stimulate glucose uptake. Additional serum glucose is converted to glycogen, the storage form of glucose, through hepatic glycogenesis. Insulin decreases production of glucose from gluconeogenesis and glycogenolysis by inhibiting glucagon release from the pancreas. The combination of these actions results in a decrease in serum blood glucose. Glucagon serves as the hormone that balances the glucose lowering effects of insulin. Glucagon controls fasting levels by stimulating gluconeogenesis and glycogenolysis in the liver. Stimulation of these mechanisms results in release of glucose, increasing serum blood glucose levels. Release of glucagon from the pancreas occurs when serum glucose levels fall below approximately 5 mmol/l (90 mg/dl) (Aronoff

hepatic ketogenesis

Decreases food intake

Decreases food intake

(prandial) insulin secretion Inhibits glucagon secretion post-

**Hormone Site of origin/production Action**

Glucagon Alpha (α)-cells of the

Table 5. Gluco-regulatory hormones

pancreas

(Aronoff et al, 2004).

Glucagon-like peptide 1 (GLP-1)

Glucosedependent insulinotropic peptide (GIP),

et al, 2004).

### **3. Risk factors**

Table 4 lists patient characteristics that may increase the risk of drug-induced hypoglycemia. Specific pharmacokinetic and pharmacodynamic drug parameters may affect the level of risk associated with the described patient characteristics.

Table 4. Risk factors for drug-induced hypoglycemia

It should be noted that the risk factors associated with drug-induced hypoglycemia are similar to the risk factors associated with the development of hypoglycemia in patients with DM. In particular it is known that advanced age, alcohol intake, and polypharmacy are all risk factors for hypoglycemia in patients with type 1 diabetes (Zammitt et al, 2005). As noted above, these are risk factors that may also place patients at risk for drug-induced hypoglycemia. In addition to the risk factors discussed above, risk factors that place patients with type 1 diabetes at risk for hypoglycemia are: caffeine intake; variations in sleep; and physical activity, in particular exercise, in relation to meals and medications (Zammitt et al, 2005). However, it is unknown how these factors affect the risk of hypoglycemia in patients with type 2 diabetes (Zammitt et al, 2005). It is known that patients with type 2 diabetes who have been taking in insulin for more than 10 years are increased risk for experiencing hypoglycemia (Zammitt et al, 2005). Obviously, the greatest concern for the development of drug-induced hypoglycemia becomes when patients have pre-exsiting diabetes and then are placed on a medication that has the potential to cause hypoglycemia.

#### **4. Glucose regulation**

Changes in serum glucose levels are a result of the following process: glucose absorption from the gastroinstestinal tract, release of stored glucose through hepatic glycogenolysis, and creation of glucose from non-glucose sources through hepatic gluconeogenesis. Glycogenolysis releases glucose through breakdown of glycogen, the stored form of glucose, and glycogenolysis creates glucose from amino acid and lactate. All three processes affect glucose levels based on proximity to meals. The rate of rise of serum glucose during and after meals is predominantly a result of the rate of gastric emptying. Rate of gastric emptying determines amount of glucose absorbed in gastrointestinal tract. During periods of fasting, glucose levels are regulated by glycogenolysis and gluconeogenesis. Glycogenolysis impacts serum glucose levels in the first 8 to 12 hours of fasting, while gluconeogenesis contributes more to glucose levels after longer periods of fasting (Aronoff et al, 2004).

Table 4 lists patient characteristics that may increase the risk of drug-induced hypoglycemia. Specific pharmacokinetic and pharmacodynamic drug parameters may affect the level of

Polypharmacy Increased risk of drug interactions resulting in

It should be noted that the risk factors associated with drug-induced hypoglycemia are similar to the risk factors associated with the development of hypoglycemia in patients with DM. In particular it is known that advanced age, alcohol intake, and polypharmacy are all risk factors for hypoglycemia in patients with type 1 diabetes (Zammitt et al, 2005). As noted above, these are risk factors that may also place patients at risk for drug-induced hypoglycemia. In addition to the risk factors discussed above, risk factors that place patients with type 1 diabetes at risk for hypoglycemia are: caffeine intake; variations in sleep; and physical activity, in particular exercise, in relation to meals and medications (Zammitt et al, 2005). However, it is unknown how these factors affect the risk of hypoglycemia in patients with type 2 diabetes (Zammitt et al, 2005). It is known that patients with type 2 diabetes who have been taking in insulin for more than 10 years are increased risk for experiencing hypoglycemia (Zammitt et al, 2005). Obviously, the greatest concern for the development of drug-induced hypoglycemia becomes when patients have pre-exsiting diabetes and then are placed on a medication that has the

Changes in serum glucose levels are a result of the following process: glucose absorption from the gastroinstestinal tract, release of stored glucose through hepatic glycogenolysis, and creation of glucose from non-glucose sources through hepatic gluconeogenesis. Glycogenolysis releases glucose through breakdown of glycogen, the stored form of glucose, and glycogenolysis creates glucose from amino acid and lactate. All three processes affect glucose levels based on proximity to meals. The rate of rise of serum glucose during and after meals is predominantly a result of the rate of gastric emptying. Rate of gastric emptying determines amount of glucose absorbed in gastrointestinal tract. During periods of fasting, glucose levels are regulated by glycogenolysis and gluconeogenesis. Glycogenolysis impacts serum glucose levels in the first 8 to 12 hours of fasting, while gluconeogenesis contributes

more to glucose levels after longer periods of fasting (Aronoff et al, 2004).

blood glucose

hypoglycemia

Decreased symptoms/decreased awareness, decreased counterregulatory response to low

risk associated with the described patient characteristics.

**Risk Factors Mechanism**

Table 4. Risk factors for drug-induced hypoglycemia

potential to cause hypoglycemia.

**4. Glucose regulation**

Renal insufficiency Decreased insulin clearance Hepatic insufficiency Decreased gluconeogenesis Decreased food intake (skipping meals) Insufficient glucose intake Excessive alcohol intake Decreased gluconeogenesis

**3. Risk factors**

Advancing age

The processes above are all regulated by glucoregulatory hormones. The hormones, their site of origin, and specific gluco-regulatory actions are listed in table 5. In addition to those listed, blood glucose levels are affected by epinephrine, cortisol, and growth hormones (Aronoff et al, 2004).

Table 5. Gluco-regulatory hormones

Insulin and glucagon play large roles in the overall regulation of blood glucose (Figure 1). Increases in serum blood glucose stimulate insulin release from the pancreas. The amount of insulin released is dependent on the level of blood glucose. Insulin is not released until blood glucose levels reach 3.3 mmol/l (59.4 mg/dl). Insulin acts to both decrease existing glucose in the blood and to decrease production of further glucose. Insulin binds to receptors on fat, muscle, and liver cells to stimulate glucose uptake. Additional serum glucose is converted to glycogen, the storage form of glucose, through hepatic glycogenesis. Insulin decreases production of glucose from gluconeogenesis and glycogenolysis by inhibiting glucagon release from the pancreas. The combination of these actions results in a decrease in serum blood glucose. Glucagon serves as the hormone that balances the glucose lowering effects of insulin. Glucagon controls fasting levels by stimulating gluconeogenesis and glycogenolysis in the liver. Stimulation of these mechanisms results in release of glucose, increasing serum blood glucose levels. Release of glucagon from the pancreas occurs when serum glucose levels fall below approximately 5 mmol/l (90 mg/dl) (Aronoff et al, 2004).

Drug-Induced Hypoglycemia 119

Of potentially greater concern are the agents which are used for indications other than hyperglycemia because the hypoglycemic episodes are often less predictable and/or unexpected. These agents often have very little or no quality evidence to document the frequency and severity of their hypoglycemic effects. This is illustrated in the systematic review of literature through 2007 conducted by The Hypoglycemia Task Force of The Endocrine Society which identified hypoglycemia associated with 164 different medications (Murad et al, 2009). This study found that no individual or class of drugs has high quality evidence supporting its impact on glucose levels, though drugs used to treat hyperglycemia were not included. Table 7 provides a list of the most commonly cited agents in the literature and their level of evidence. Level of evidence was defined by use of the GRADE approach to literature evaluation. Available evidence was evaluated for quality of study design, strength of association of the medication to the reported adverse effects, and

Indomethacin Increase insulin secretion from pancreas, decrease in

Pentamadine Increased insulin secretion from pancreas through cell

Increase insulin sensitivity

glucose uptake in the periphery

Beta blockers Mask signs/symptoms of hypoglycemia, increase in

Table 7. Strength of evidence of drug-induced hypoglycemia and proposed mechanisms

damage Quinine Increased insulin secretion from pancreas

Ethanol Decrease in gluconeogenesis in the liver

Sulfamethoxazole Increase insulin secretion from pancreas

May increase insulin secretion from pancreas

increase in glucose uptake in periphery

insulin clearance, decrease in gluconeogenesis, and

**Anti-diabetic agents**

Secratagogues (non-sulfonylurea)

quantity of evidence available (Murad et al, 2009).

Fluoroquinolones (gatifloxacin) Unclear

Lithium Unclear Propoxyphene Unclear

**Agent/Class Mechanism of hypoglycemia**

**Agent/Class Mechanism of hypoglycemia**

**Moderate Quality Evidence**

**Poor Quality Evidence**

Angiotensin Converting Enzyme Inhibitors (ACEIs)

(Murad, et al, 2009).

Table 6. Anti-diabetic agents with greatest evidence of causing hypoglycaemia

Exenatide Insulin Pramlintide

Sitagliptin Sulfonylureas

Fig. 1. Glucose regulation (Dugi K, 2009)

#### **5. Causative agents**

5.1 There are a number of agents implicated in causing hypoglycemia; however, the level of evidence available varies significantly amongst agents. The most highly documented druginduced hypoglycemia occurs with medications used to treat hyperglycemia. The specific agents and classes are included in table 6 below.

5.1 There are a number of agents implicated in causing hypoglycemia; however, the level of evidence available varies significantly amongst agents. The most highly documented druginduced hypoglycemia occurs with medications used to treat hyperglycemia. The specific

Fig. 1. Glucose regulation (Dugi K, 2009)

agents and classes are included in table 6 below.

**5. Causative agents**

Table 6. Anti-diabetic agents with greatest evidence of causing hypoglycaemia

Of potentially greater concern are the agents which are used for indications other than hyperglycemia because the hypoglycemic episodes are often less predictable and/or unexpected. These agents often have very little or no quality evidence to document the frequency and severity of their hypoglycemic effects. This is illustrated in the systematic review of literature through 2007 conducted by The Hypoglycemia Task Force of The Endocrine Society which identified hypoglycemia associated with 164 different medications (Murad et al, 2009). This study found that no individual or class of drugs has high quality evidence supporting its impact on glucose levels, though drugs used to treat hyperglycemia were not included. Table 7 provides a list of the most commonly cited agents in the literature and their level of evidence. Level of evidence was defined by use of the GRADE approach to literature evaluation. Available evidence was evaluated for quality of study design, strength of association of the medication to the reported adverse effects, and quantity of evidence available (Murad et al, 2009).

Table 7. Strength of evidence of drug-induced hypoglycemia and proposed mechanisms (Murad, et al, 2009).

Drug-Induced Hypoglycemia 121

concomitant use of hypoglycemic medications, advanced age, and decreased renal function

Indomethacin belongs to the class of agents called non-steroidal anti-inflammatory drugs (NSAIDs). Anti-inflammatory agents, including salicylates, are all thought to increase risk of hypoglycemia, with indomethacin having the greatest evidence, likely due to the population being treated. Though often used for osteoarthritis and other inflammatory conditions, indomethacin may also be used to close a patent ductus arteriosis in neonates, often in those born prematurely. Increases in pancreatic insulin secretion, decreases in insulin clearance, increases in glucose utilization in the periphery, and decreases in gluconeogenesis all appear to contribute to the hypoglycemic effects of these drugs. Less than three per cent of neonates exposed to therapeutic levels of intravenous indomethacin for patent ductus arteriosis experience hypoglycemia (Product Information: Indocin, 2010). Whether this effect is dose-related is unclear; however, the risk may be significantly decreased by use of a

Pentamidine is an anti-fungal agent which exhibits its effects through inhibition of microbial nuclear metabolism. Direct cytotoxic effects on beta cells of the pancreas results in increased secretion of insulin. This early release of insulin is due to the lytic effects on the cell which result in cell death. This can ultimately result in insulin-dependent diabetes as a result of this cell loss (Pandit et al, 1993). Pentamidine is associated with a 6-40% risk of hypoglycemia in patients receiving intravenous or intramuscular administration. Hypoglycemia is most commonly seen in patients with acquired immune deficiency syndrome (AIDS) treated for *Pneumocystis carinii* (Murad et al, 2009 & Product Information: Pentin, 2008) (Product Information: Pentam, 2008 & Product Information: Nebupent, 2008). The risk of hypoglycemia and resultant pancreatic damage associated with pentamidine is greater with higher doses, higher cumulative doses, and prolonged use (Pandit et al, 1993). There also appears to be increased risk with use of pentamidine mesylate compared to

Quinine is an anti-malarial agent used acutely for systemic and cerebral disease. More than 300 cases of hypoglycemia have been reported with quinine therapy and 30 clinical studies have demonstrated similar findings (Murad et al, 2009). The crux of the hypoglycemic effects of quinine appear to be the result of increased insulin secretion from beta cells. Though this is most common in patients infected with malaria, there are reports of quinine-induced hypoglycemia in patients without malaria. Patients with malaria often exhibit more severe or sustained hypoglycemia since the organism responsible for malaria, *Plasmodium falciparum,* independently lowers glucose levels. There is also an increased risk of hypoglycemia with higher doses of quinine and with infusion times of intravenous doses of less than one hour. Manufacturers recommend intravenous infusions occur over four hours to minimize risk of hypoglycemia (Product Information: Qualaquin, 2010). Quinine-induced hypoglycemia can be resistant to traditional therapy with glucose and glucagon; however, treatment with octreotide has been shown to be beneficial (Pandit

(Frothingham, 2005; Product Information: Tequin, 2006; Yip & Lee, 2006).

concomitant infusion of intravenous glucose (Hosono, 1999).

**5.2.2 Indomethacin**

**5.2.3 Pentamidine**

**5.2.4 Quinine**

et al, 1993).

pentamidine isothionate (Waskin, 1996).

Drug-induced hypoglycemia may be a result of direct changes to glucose homeostasis or indirect effects on a patient's ability to recognize onset of hypoglycemia. Changes that affect glucose homeostasis include direct increase in insulin secretion from the pancreas, indirect increase in insulin secretion through decreased degradation of incretin hormones (GLP-1 and GIP), cytotoxic effects on pancreatic cells leading to increase insulin release, decrease in gluconeogenesis, increase in glucose utilization and storage, decrease in glucagon release from the pancreatic α cells, and decreased gastric emptying (Pandit et al, 1993). Many agents affect glucose homeostasis through a combination of these mechanisms. Location of mechanism is exhibited in table 8.

Table 8. Location of action of agents implicated in drug-induced hypoglycemia

#### **5.2 Specific agents**

Specific agents, including risk factors and frequency of hypoglycemic events, are discussed below.

#### **5.2.1 Fluoroquinolones**

Fluoroquinolones are antibiotics which exhibit their antimicrobial activity through inhibition of DNA gyrase and topoisomerase IV, enzymes involved in bacterial cell division (Product Information: Tequin, 2006). The class includes the following agents: ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin, and rofloxacin. Though there are reports of hypoglycemia with most agents in this class, a majority of the evidence with fluoroquinolone-induced hypoglycemia is with gatifloxacin (Murad et al, 2009). The exact mechanism of this hypoglycemic effect is not clear; however, it is proposed that fluoroquinolones increase insulin secretion from the pancreas and may have a pharmacokinetic or pharmacodynamic interaction with various antidiabetic agents, including sulfonylureas. The adverse effect does not appear dose-related and presents typically within the first three days of therapy for less severe hypoglycemia (Frothingham, 2005; Gajjar, et al, 2000; Park-Wyllie et al, 2006; Product Information: Tequin, 2006). More severe episodes, specifically those requiring hospitalization or prolonged hospitalization, are more common after three days of therapy. Hypoglycemia has been reported with intravenous and oral therapies in both outpatient and inpatient settings, and discontinuation of the medication is often required to resolve the glucose abnormalities (Murad et al, 2009). Though new onset diabetes has been reported, risk factors for patients who are more likely to experience hypoglycemic episodes are: pre-existing diabetes,

Drug-induced hypoglycemia may be a result of direct changes to glucose homeostasis or indirect effects on a patient's ability to recognize onset of hypoglycemia. Changes that affect glucose homeostasis include direct increase in insulin secretion from the pancreas, indirect increase in insulin secretion through decreased degradation of incretin hormones (GLP-1 and GIP), cytotoxic effects on pancreatic cells leading to increase insulin release, decrease in gluconeogenesis, increase in glucose utilization and storage, decrease in glucagon release from the pancreatic α cells, and decreased gastric emptying (Pandit et al, 1993). Many agents affect glucose homeostasis through a combination of these mechanisms. Location of

**Pancreas Liver Periphery Kidney Gut**

Table 8. Location of action of agents implicated in drug-induced hypoglycemia

Specific agents, including risk factors and frequency of hypoglycemic events, are discussed

Fluoroquinolones are antibiotics which exhibit their antimicrobial activity through inhibition of DNA gyrase and topoisomerase IV, enzymes involved in bacterial cell division (Product Information: Tequin, 2006). The class includes the following agents: ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin, and rofloxacin. Though there are reports of hypoglycemia with most agents in this class, a majority of the evidence with fluoroquinolone-induced hypoglycemia is with gatifloxacin (Murad et al, 2009). The exact mechanism of this hypoglycemic effect is not clear; however, it is proposed that fluoroquinolones increase insulin secretion from the pancreas and may have a pharmacokinetic or pharmacodynamic interaction with various antidiabetic agents, including sulfonylureas. The adverse effect does not appear dose-related and presents typically within the first three days of therapy for less severe hypoglycemia (Frothingham, 2005; Gajjar, et al, 2000; Park-Wyllie et al, 2006; Product Information: Tequin, 2006). More severe episodes, specifically those requiring hospitalization or prolonged hospitalization, are more common after three days of therapy. Hypoglycemia has been reported with intravenous and oral therapies in both outpatient and inpatient settings, and discontinuation of the medication is often required to resolve the glucose abnormalities (Murad et al, 2009). Though new onset diabetes has been reported, risk factors for patients who are more likely to experience hypoglycemic episodes are: pre-existing diabetes,

Beta

adrenergic antagonists Angiotensin converting enzyme (ACE) inhibitors Indomethacin Insulin

Indomethacin Pramlintide

mechanism is exhibited in table 8.

 Ethanol Indomethacin Exenatide Pramlintide Sitagliptin

 Pentamidine Fluoroquinolones Sulfamethoxazole

**5.2 Specific agents**

**5.2.1 Fluoroquinolones**

below.

 Quinine Indomethacin Exenatide Sulfonylureas Non-sulfonylurea secretagogues Sitagliptin

concomitant use of hypoglycemic medications, advanced age, and decreased renal function (Frothingham, 2005; Product Information: Tequin, 2006; Yip & Lee, 2006).

#### **5.2.2 Indomethacin**

Indomethacin belongs to the class of agents called non-steroidal anti-inflammatory drugs (NSAIDs). Anti-inflammatory agents, including salicylates, are all thought to increase risk of hypoglycemia, with indomethacin having the greatest evidence, likely due to the population being treated. Though often used for osteoarthritis and other inflammatory conditions, indomethacin may also be used to close a patent ductus arteriosis in neonates, often in those born prematurely. Increases in pancreatic insulin secretion, decreases in insulin clearance, increases in glucose utilization in the periphery, and decreases in gluconeogenesis all appear to contribute to the hypoglycemic effects of these drugs. Less than three per cent of neonates exposed to therapeutic levels of intravenous indomethacin for patent ductus arteriosis experience hypoglycemia (Product Information: Indocin, 2010). Whether this effect is dose-related is unclear; however, the risk may be significantly decreased by use of a concomitant infusion of intravenous glucose (Hosono, 1999).

#### **5.2.3 Pentamidine**

Pentamidine is an anti-fungal agent which exhibits its effects through inhibition of microbial nuclear metabolism. Direct cytotoxic effects on beta cells of the pancreas results in increased secretion of insulin. This early release of insulin is due to the lytic effects on the cell which result in cell death. This can ultimately result in insulin-dependent diabetes as a result of this cell loss (Pandit et al, 1993). Pentamidine is associated with a 6-40% risk of hypoglycemia in patients receiving intravenous or intramuscular administration. Hypoglycemia is most commonly seen in patients with acquired immune deficiency syndrome (AIDS) treated for *Pneumocystis carinii* (Murad et al, 2009 & Product Information: Pentin, 2008) (Product Information: Pentam, 2008 & Product Information: Nebupent, 2008). The risk of hypoglycemia and resultant pancreatic damage associated with pentamidine is greater with higher doses, higher cumulative doses, and prolonged use (Pandit et al, 1993). There also appears to be increased risk with use of pentamidine mesylate compared to pentamidine isothionate (Waskin, 1996).

#### **5.2.4 Quinine**

Quinine is an anti-malarial agent used acutely for systemic and cerebral disease. More than 300 cases of hypoglycemia have been reported with quinine therapy and 30 clinical studies have demonstrated similar findings (Murad et al, 2009). The crux of the hypoglycemic effects of quinine appear to be the result of increased insulin secretion from beta cells. Though this is most common in patients infected with malaria, there are reports of quinine-induced hypoglycemia in patients without malaria. Patients with malaria often exhibit more severe or sustained hypoglycemia since the organism responsible for malaria, *Plasmodium falciparum,* independently lowers glucose levels. There is also an increased risk of hypoglycemia with higher doses of quinine and with infusion times of intravenous doses of less than one hour. Manufacturers recommend intravenous infusions occur over four hours to minimize risk of hypoglycemia (Product Information: Qualaquin, 2010). Quinine-induced hypoglycemia can be resistant to traditional therapy with glucose and glucagon; however, treatment with octreotide has been shown to be beneficial (Pandit et al, 1993).

Drug-Induced Hypoglycemia 123

captopril (Murad et al, 2009; Herings et al, 1995). All members of this class are listed in table 10 below. Though the mechanism for this drug-induced hypoglycaemia is not well defined, it is proposed that the increase in bradykinins associated with ACE inhibitor use may cause an increase in insulin sensitivity (Pandit et al, 1993; Vuorinen-Markkola & Yki-Jarvinen, 1995). One study by Pollare, et al, suggests that captopril increases glucose utilization in the periphery compared to use of hydrochlorothiazide (Pollare et al, 1989); however, Wiggam, et al, demonstrates in one study that ACE inhibitors have no impact on hepatic or peripheral insulin sensitivity (Wiggam et al, 1998). Because of the contradicting information available, the actual impact of ACE inhibitors on blood glucose is not clear. ACE inhibitor therapy is a mainstay of hypertension, diabetes, and cardiovascular disease management. To date, there is insufficient evidence available to warrant discontinuation of this therapy in patients at risk for hypoglycemia with these disease states; however, in patients with suspected captopril-induced hypoglycemia, switching to another ACE inhibitor is a reasonable

**ACE Inhibitors**

Despite the poor level of evidence, ethanol has been touted as one of the most common causes of drug-induced hypoglycaemia in the United States (Pandit et al, 1993). The proposed mechanism is a direct suppression of gluconeogenesis in the liver, a process that typically occurs in more long-standing fasting states. Some studies suggest that this hypoglycemic potential is present in both occasional and chronic alcohol consumers and is more common with use of non-carbohydrate laden drinks (Pandit et al, 1993). Because of

One easy way to prevent drug-induced hypoglycemia is to avoid the medication that poses the potential for drug-induced hypoglycemia in patients that are at high risk for drug-induced hypoglycemia. Unfortunately, it may not be practical to avoid certain medications that may cause drug-induced hypoglycemia. As when deciding to use any medication, weigh the

this, patients at greater risk for hypoglycemia should avoid consuming alcohol.

benefit of using the medication versus risk, in this case drug-induced hypoglycemia.

Benazepril Captopril Enalapril Fosinopril Lisinopril Moexipril Perindopril Quinapril Ramipril Trandolapril

Table 10. Angiotensin Converting Enzyme (ACE) Inhibitors

recommendation.

**5.2.7 Ethanol**

**6. Prevention**

#### **5.2.5 Beta blockers**

Non-selective beta-adrenergic antagonists, also known as beta blockers, are vasodilators which are often used to treat hypertension and cardiac disease. A list of non-selective beta blockers is provided in table 9 below. These agents have been linked with hypoglycemic effects in patients with and without diabetes (Murad et al, 2009). Oral formulations are most commonly the culprit; however, hypoglycemia associated with topical formulations is documented (Pandit et al, 1993). Though there are numerous reports of hypoglycemia associated with beta blockers , the quality of the data is limited. Murad, et al, theorizes that the high numbers of reports are a representation of the frequency of use of these agents more than the frequency of the actual hypoglycemic events (Murad et al, 2009).

There are two proposed mechanisms for this hypoglycemic effect in beta blockers. First, there is a blunting of the signs and symptoms of hypoglycemia (White, 2007). The exception to this blunting effect is sweating, an important educational point for all patients (Product Information: Innopran XL, 2010). The second mechanism is a direct potentiation of the effects of insulin. This heightened insulin effect increases glucose utilization in the periphery and inhibits lipolysis. Further, there is a diminished physiologic response to hypoglycemia in patient receiving beta blockers, specifically a decrease in glycogenolysis and gluconeogenesis (Pandit et al, 1993 & White, 2007). Patients at greatest risk for hypoglycemia with beta blockers include patients with hepatic disease, patients on hemodialysis, neonates, and patients with type 1 diabetes (Product Information: Innopran XL, 2010). Use of selective beta blockers, such as atenolol, metoprolol, and bisoprolol are thought to have a decreased risk of hypoglycaemia and may be a reasonable alternative to patients unable to tolerate non-selective agents (Pandit et al, 1993).

Table 9. Non-selective beta-adrenergic antagonists (beta blockers)

#### **5.2.6 ACE inhibitors**

Angiotensin converting enzyme (ACE) inhibitors are a class of drugs that are typically used for hypertension and cardiovascular disease. Eleven studies document the potential for ACEI inhibitor-associated hypoglycemia, and a majority of these are with the use of

Non-selective beta-adrenergic antagonists, also known as beta blockers, are vasodilators which are often used to treat hypertension and cardiac disease. A list of non-selective beta blockers is provided in table 9 below. These agents have been linked with hypoglycemic effects in patients with and without diabetes (Murad et al, 2009). Oral formulations are most commonly the culprit; however, hypoglycemia associated with topical formulations is documented (Pandit et al, 1993). Though there are numerous reports of hypoglycemia associated with beta blockers , the quality of the data is limited. Murad, et al, theorizes that the high numbers of reports are a representation of the frequency of use of these agents

There are two proposed mechanisms for this hypoglycemic effect in beta blockers. First, there is a blunting of the signs and symptoms of hypoglycemia (White, 2007). The exception to this blunting effect is sweating, an important educational point for all patients (Product Information: Innopran XL, 2010). The second mechanism is a direct potentiation of the effects of insulin. This heightened insulin effect increases glucose utilization in the periphery and inhibits lipolysis. Further, there is a diminished physiologic response to hypoglycemia in patient receiving beta blockers, specifically a decrease in glycogenolysis and gluconeogenesis (Pandit et al, 1993 & White, 2007). Patients at greatest risk for hypoglycemia with beta blockers include patients with hepatic disease, patients on hemodialysis, neonates, and patients with type 1 diabetes (Product Information: Innopran XL, 2010). Use of selective beta blockers, such as atenolol, metoprolol, and bisoprolol are thought to have a decreased risk of hypoglycaemia and may be a reasonable alternative to

more than the frequency of the actual hypoglycemic events (Murad et al, 2009).

patients unable to tolerate non-selective agents (Pandit et al, 1993).

Alprenolol Bucindolol Carteolol Nadolol Penbutolol Pindolol Propranolol Sotalol Timolol

Carvedilol Labetalol

**5.2.6 ACE inhibitors**

**Non-selective beta-adrenergic antagonists**

**Non-selective beta-adrenergic antagonists with**

Angiotensin converting enzyme (ACE) inhibitors are a class of drugs that are typically used for hypertension and cardiovascular disease. Eleven studies document the potential for ACEI inhibitor-associated hypoglycemia, and a majority of these are with the use of

**additional alpha antagonism:**

Table 9. Non-selective beta-adrenergic antagonists (beta blockers)

**5.2.5 Beta blockers**

captopril (Murad et al, 2009; Herings et al, 1995). All members of this class are listed in table 10 below. Though the mechanism for this drug-induced hypoglycaemia is not well defined, it is proposed that the increase in bradykinins associated with ACE inhibitor use may cause an increase in insulin sensitivity (Pandit et al, 1993; Vuorinen-Markkola & Yki-Jarvinen, 1995). One study by Pollare, et al, suggests that captopril increases glucose utilization in the periphery compared to use of hydrochlorothiazide (Pollare et al, 1989); however, Wiggam, et al, demonstrates in one study that ACE inhibitors have no impact on hepatic or peripheral insulin sensitivity (Wiggam et al, 1998). Because of the contradicting information available, the actual impact of ACE inhibitors on blood glucose is not clear. ACE inhibitor therapy is a mainstay of hypertension, diabetes, and cardiovascular disease management. To date, there is insufficient evidence available to warrant discontinuation of this therapy in patients at risk for hypoglycemia with these disease states; however, in patients with suspected captopril-induced hypoglycemia, switching to another ACE inhibitor is a reasonable recommendation.

Table 10. Angiotensin Converting Enzyme (ACE) Inhibitors

#### **5.2.7 Ethanol**

Despite the poor level of evidence, ethanol has been touted as one of the most common causes of drug-induced hypoglycaemia in the United States (Pandit et al, 1993). The proposed mechanism is a direct suppression of gluconeogenesis in the liver, a process that typically occurs in more long-standing fasting states. Some studies suggest that this hypoglycemic potential is present in both occasional and chronic alcohol consumers and is more common with use of non-carbohydrate laden drinks (Pandit et al, 1993). Because of this, patients at greater risk for hypoglycemia should avoid consuming alcohol.

#### **6. Prevention**

One easy way to prevent drug-induced hypoglycemia is to avoid the medication that poses the potential for drug-induced hypoglycemia in patients that are at high risk for drug-induced hypoglycemia. Unfortunately, it may not be practical to avoid certain medications that may cause drug-induced hypoglycemia. As when deciding to use any medication, weigh the benefit of using the medication versus risk, in this case drug-induced hypoglycemia.

Drug-Induced Hypoglycemia 125

blood glucose

hypoglycemia

hypoglycemia

Discussion of timing of blood glucose

monitoring and target levels

Monitor for signs/symptoms of

Review appropriate treatment of

Monitor blood glucose levels at clinic visits Demonstration of self-monitoring of

Table 12. Monitoring Points When Patients Are Taking Medications with a Potential to

When measures to prevent drug-induced hypoglycemia do not work or when appropriate prevention measures were not able to be undertaken, hypoglycemia, especially symptomatic hypoglycemia, must be treated. Specific, evidence-based recommendations for management of drug-induced hypoglycemia are not readily available. In the absence of guidelines for drug-induced hypoglycemia, patients who experience this should be treated according to readily accepted guidelines for managing hypoglycemia in patients with diabetes (Cryer et

As described in the section "Defining Hypoglycemia," patients may experience a variety of nonspecific symptoms (neurogenic symptoms and neuroglycopenic symptoms) as well as physical signs than can be attributed to hypoglycemia. Since there are not clear distinctions in hypoglycemic symptoms that occur regardless of the source of the symptom – druginduced, diabetes mellitus, or another disease state, it is important that patients and caregivers be knowledgeable of the signs and symptoms of hypoglycemia. Sometimes friends and family members are the ones that recognize the patient is experiencing symptoms that can be attributed to hypoglycemia (Cryer et al, 2003). In particular they may notice changes in the patient's behavior, mood, speech, or train of thought as the patient is

When hypoglycemia is suspected it is important to recognize that the signs and symptoms a patient may complain of or present with are nonspecific and often other causes of the signs and symptoms must be ruled out. In 2009 the Endocrine Society released a clinical practice guideline specifying a workup strategy for patients who experience hypoglycemia in the absence of DM (Cryer, et al, 2009). The guidelines instruct the healthcare provider to review the patient's past medical history, physical exam, review of systems, laboratory data, and medications – current and past. These guidelines detail additional workup to undertake if

**Prescriber Considerations Patient Education Points**

Inquire about experiences with hypoglycemia,

Weigh the patient at clinic visits and review the

al, 2009, American Diabetes Association, 2011).

**7.1 Signs and symptoms of hypoglycemia**

trying to communicate with them.

**7.2 Differential diagnosis**

including specific signs/symptoms

Cause Drug-Induced Hypoglycemia

trend

**7. Management**

If avoiding the agent is not possible, attempt to minimize the risk of hypoglycemia by keeping in mind the following restrictions. Use extended-release/sustained-released products if that is an option for the medication needed (Pandit et al, 1993). Reinforce with patients the need to avoid alcohol intake (Pandit et al, 1993). Minimizing the lenth of time and dose of an offending agent may also be beneficial. Since hypoglycemia awareness is largely reliant on patient perception of the signs and symptoms of hypoglycemia, education is key (Cryer et al, 2003). Therefore, it is important to review the signs and symptoms of hypoglycemia with patients and caregivers. One way to monitor patients for evidence of hypoglycemia is to monitor their blood glucose concentrations, which is especially in important in patients with pre-existing diabetes. Blood glucose should be carefully monitored with initiation, dose changes, or discontinuation of any medication in patients with diabetes. It is usually recommended for patients to regularly check their fasting blood glucose readings during the initiation of a medication that can cause drug-induced hypoglycemia. The healthcare provider can make patient specific recommendations on how often to monitor blood glucose based on the patient's underlying risk for hypoglycemia (e.g. patients already taking 1 or more agents that can cause drug-induced hypoglycemia or those patients with a diagnosis of diabetes) as well as any manufacturer recommendations. In addition to instructing the patient to monitor and record their blood glucose levels at home, it is helpful for a healthcare provider to review the history of the patient's blood glucose levels at every visit and ask about signs and symptoms of hypoglycemia. Tracking the patient's weight and reviewing the trend over the time the patient is taking a potentially offending agent may also provide insight into whether the patient is experiencing asymptomatic hypoglycemia, especially when reviewed with the patient's fasting blood glucose levels. When at all possible, patients should not be taking multiple agents that may cause drug-induced hypoglycemia. Healthcare providers should also be diligent to review a patient's medication profile for drug interactions, pharmacokinetics and pharmacodynamic, with potentially offending hypoglycemic agents. Tables 11 and 12 provide a summary of points to remember when prescribing medications with a potential for drug-induced hypoglycemia.

#### Prescribing Considerations

Use extended or sustained release products when possible

Avoid alcohol intake

Minimize the length of time on an offending agent

Utilize the lowest effective dose of the offending agent

Avoid having multiple medications in the patient's profile that can cause hypoglycemia

Screen the patient, s medication profile for drug interactions – pharmacokinetic and pharmacodynamic

Table 11. Specific Prescribing Considerations When Prescribing Medications with a Potential to Cause Drug-Induced Hypoglycemia

If avoiding the agent is not possible, attempt to minimize the risk of hypoglycemia by keeping in mind the following restrictions. Use extended-release/sustained-released products if that is an option for the medication needed (Pandit et al, 1993). Reinforce with patients the need to avoid alcohol intake (Pandit et al, 1993). Minimizing the lenth of time and dose of an offending agent may also be beneficial. Since hypoglycemia awareness is largely reliant on patient perception of the signs and symptoms of hypoglycemia, education is key (Cryer et al, 2003). Therefore, it is important to review the signs and symptoms of hypoglycemia with patients and caregivers. One way to monitor patients for evidence of hypoglycemia is to monitor their blood glucose concentrations, which is especially in important in patients with pre-existing diabetes. Blood glucose should be carefully monitored with initiation, dose changes, or discontinuation of any medication in patients with diabetes. It is usually recommended for patients to regularly check their fasting blood glucose readings during the initiation of a medication that can cause drug-induced hypoglycemia. The healthcare provider can make patient specific recommendations on how often to monitor blood glucose based on the patient's underlying risk for hypoglycemia (e.g. patients already taking 1 or more agents that can cause drug-induced hypoglycemia or those patients with a diagnosis of diabetes) as well as any manufacturer recommendations. In addition to instructing the patient to monitor and record their blood glucose levels at home, it is helpful for a healthcare provider to review the history of the patient's blood glucose levels at every visit and ask about signs and symptoms of hypoglycemia. Tracking the patient's weight and reviewing the trend over the time the patient is taking a potentially offending agent may also provide insight into whether the patient is experiencing asymptomatic hypoglycemia, especially when reviewed with the patient's fasting blood glucose levels. When at all possible, patients should not be taking multiple agents that may cause drug-induced hypoglycemia. Healthcare providers should also be diligent to review a patient's medication profile for drug interactions, pharmacokinetics and pharmacodynamic, with potentially offending hypoglycemic agents. Tables 11 and 12 provide a summary of points to remember when prescribing medications with a potential for drug-induced

hypoglycemia.

Prescribing Considerations

Avoid alcohol intake

Screen the patient,

pharmacodynamic

to Cause Drug-Induced Hypoglycemia

Use extended or sustained release products when possible

Minimize the length of time on an offending agent

Utilize the lowest effective dose of the offending agent

Avoid having multiple medications in the patient's profile that can cause hypoglycemia

Table 11. Specific Prescribing Considerations When Prescribing Medications with a Potential

s medication profile for drug interactions – pharmacokinetic and

Table 12. Monitoring Points When Patients Are Taking Medications with a Potential to Cause Drug-Induced Hypoglycemia

### **7. Management**

When measures to prevent drug-induced hypoglycemia do not work or when appropriate prevention measures were not able to be undertaken, hypoglycemia, especially symptomatic hypoglycemia, must be treated. Specific, evidence-based recommendations for management of drug-induced hypoglycemia are not readily available. In the absence of guidelines for drug-induced hypoglycemia, patients who experience this should be treated according to readily accepted guidelines for managing hypoglycemia in patients with diabetes (Cryer et al, 2009, American Diabetes Association, 2011).

#### **7.1 Signs and symptoms of hypoglycemia**

As described in the section "Defining Hypoglycemia," patients may experience a variety of nonspecific symptoms (neurogenic symptoms and neuroglycopenic symptoms) as well as physical signs than can be attributed to hypoglycemia. Since there are not clear distinctions in hypoglycemic symptoms that occur regardless of the source of the symptom – druginduced, diabetes mellitus, or another disease state, it is important that patients and caregivers be knowledgeable of the signs and symptoms of hypoglycemia. Sometimes friends and family members are the ones that recognize the patient is experiencing symptoms that can be attributed to hypoglycemia (Cryer et al, 2003). In particular they may notice changes in the patient's behavior, mood, speech, or train of thought as the patient is trying to communicate with them.

#### **7.2 Differential diagnosis**

When hypoglycemia is suspected it is important to recognize that the signs and symptoms a patient may complain of or present with are nonspecific and often other causes of the signs and symptoms must be ruled out. In 2009 the Endocrine Society released a clinical practice guideline specifying a workup strategy for patients who experience hypoglycemia in the absence of DM (Cryer, et al, 2009). The guidelines instruct the healthcare provider to review the patient's past medical history, physical exam, review of systems, laboratory data, and medications – current and past. These guidelines detail additional workup to undertake if

Drug-Induced Hypoglycemia 127

patient's risk for severe hypoglycemia. If a patient is taking multiple agents that can alter their blood glucose or if they have multiple risk factors for hypoglycemia then it would be reasonable for the patient to be provided with a prescription for a glucagon kit and for their caregiver(s) to receive appropriate training. If the patient's hypoglycemia is severe enough to warrant attention of emergency personnel, then additional measures to raise their blood

In addition to quickly trying to reverse the patient's hypoglycemia once it has occurred, a plan should be developed to prevent future episodes of hypoglycemia. As discussed in the "Prevention" section in Table 12, prescribing of the medication suspected to be causing hypoglycemia should be continued under close supervision. Providers should recognize that if offending drugs must be continued that there may need to be decreases in the dose, duration, or timing of administration. Once an episode of hypoglycemia has occurred, afterwards is an appropriate time to re-visit how the situation was managed and to make sure there is an action plan for any future episodes. A summary of general principles of the

Recognition of signs and symptoms of hypoglycemia – differentiation between mild –

Appropriate treatment of hypoglycemia – patient-treated with a quick acting glucose source versus caregiver assisted with glucagon or healthcare provider treatment with