Effects of administration of caffeine on metabolic variables in neonatal pigs with peripartum asphyxia

Héctor Orozco-Gregorio Department of Animal Production and Agriculture, Área de Investigación: Ecodesarrollo de la Producción Animal, Universidad Autónoma Metropolitana, Xochimilco, CP 04960, México DF.

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Daniel Mota-Rojas Department of Animal Production and Agriculture, Área de Investigación: Ecodesarrollo de la Producción Animal, Universidad Autónoma Metropolitana, Xochimilco, CP 04960, México DF.

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Herlinda Bonilla-Jaime Department of Reproductive Biology, Universidad Autónoma Metropolitana, Iztapalapa, CP 09340, México DF, Mexico.

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María E. Trujillo-Ortega Department of Animal Medicine and Production, Swine, Faculty of Veterinary and Animal Production, Universidad Nacional Autónoma de México, CP 04510, México DF, Mexico.

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Marcelino Becerril-Herrera Academic Unit of Agro-hydraulic Engineering, Benemérita Universidad Autónoma de Puebla, CP 72000, Puebla, México.

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Rafael Hernández-González Department of Experimental Research and Animal Resources, Instituto Nacional de Ciencias Médicas y Nutrición Salvador-Zubirán, CP 14000, México DF, Mexico.

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Dina Villanueva-García Division of Neo-natology, Hospital Infantil de México Federico Gómez, CP 06720, México DF, Mexico.

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Abstract

Objective—To determine effects of 2 doses of caffeine on metabolic variables in neonata pigs with peripartum asphyxia

Animals—180 neonatal pigs

Procedures—Neonatal pigs were assigned to 2 groups (groups P and F) on the basis of results for a vitality scale (passed or failed, respectively). Within each group, there were 3 subgroups of 30 pigs each. Within each group, the 3 subgroups received a placebo that consisted of an empty gelatin capsule, a gelatin capsule that contained 20 mg of caffeine, and a gelatin capsule that contained 35 mg of caffeine, respectively; all capsules were administered orally (0 hours). Blood samples were collected immediately before and 24 hours after capsule administration.

Results—Pigs in groups P and F that received 20 or 35 mg of caffeine had significant increases in triglyceride concentrations. All pigs in groups P and F had a significant decrease in lactate concentrations, although the placebo-treated pigs in group F had larger decreases than did the group F pigs treated with 20 or 35 mg of caffeine. Glucose concentrations increased significantly in group F pigs treated with 20 or 35 mg of caffeine (30% and 50%, respectively), whereas glucose concentrations remained unchanged in group P pigs. In pigs treated with 35 mg of caffeine, the final weight obtained for group F was approximately 8% lower than that obtained for group P

Conclusions and Clinical Relevance—Administering caffeine immediately after birth to neonatal pigs with severe oxygen restriction resulted in significant improvements in metabolic variables. (Am J Vet Res 2010;71:1214-1219)

Abstract

Objective—To determine effects of 2 doses of caffeine on metabolic variables in neonata pigs with peripartum asphyxia

Animals—180 neonatal pigs

Procedures—Neonatal pigs were assigned to 2 groups (groups P and F) on the basis of results for a vitality scale (passed or failed, respectively). Within each group, there were 3 subgroups of 30 pigs each. Within each group, the 3 subgroups received a placebo that consisted of an empty gelatin capsule, a gelatin capsule that contained 20 mg of caffeine, and a gelatin capsule that contained 35 mg of caffeine, respectively; all capsules were administered orally (0 hours). Blood samples were collected immediately before and 24 hours after capsule administration.

Results—Pigs in groups P and F that received 20 or 35 mg of caffeine had significant increases in triglyceride concentrations. All pigs in groups P and F had a significant decrease in lactate concentrations, although the placebo-treated pigs in group F had larger decreases than did the group F pigs treated with 20 or 35 mg of caffeine. Glucose concentrations increased significantly in group F pigs treated with 20 or 35 mg of caffeine (30% and 50%, respectively), whereas glucose concentrations remained unchanged in group P pigs. In pigs treated with 35 mg of caffeine, the final weight obtained for group F was approximately 8% lower than that obtained for group P

Conclusions and Clinical Relevance—Administering caffeine immediately after birth to neonatal pigs with severe oxygen restriction resulted in significant improvements in metabolic variables. (Am J Vet Res 2010;71:1214-1219)

In pigs, 40% of all preweaning deaths occur at birth or during the first day after birtha; these deaths are likely to be closely associated with the process of fetal asphyxia.1,2 In addition, approximately 14% of all live-born baby pigs have low postnatal viability associated with a decrease in the flow of blood and oxygen to the fetus during birth.3 This low viability significantly increases the time it requires for a neonatal pig to locate a teat of the dam for the first time and begin suckling and may be related to possible neurologic damage caused by the decrease in blood flow to the brain of neonatal pigs during in utero asphyxia.4,5

To prevent and reverse possible damage from asphyxia, several protocols have been developed, all of which are oriented toward improving the viability of neonatal pigs. Administration of oxygen (40%) to baby pigs immediately after birth causes an increase in blood pH and a decrease in blood lactate concentrations.6 These physiologic changes have also been reported in another study5 of neonatal pigs that had evidence of severe intrapartum asphyxia and that were maintained under controlled environmental and feeding conditions for 5 days after birth. In both of those studies,5,6 improvement in several physiometabolic markers was attributed to the rapid provision of oxygen to the neonatal pigs immediately after birth, which stimulated oxidative metabolism and the complete aerobic oxidation of glucose and generated an additional quantity of ATP7 and a decrease in the amount of lactate in the blood.8 In human obstetrics, the treatment of neonatal apnea related to asphyxia during birth has involved the use of caffeine as a nonspecific inhibitor of adenosine receptors,9 which stimulates respiration.10 However, the veterinary medical literature does not contain therapeutic protocols that have been used successfully to stimulate the respiratory nervous center (which is inhibited during asphyxia in neonatal pigs) and that would therefore increase the survival rate. Thus, the study reported here was conducted to determine the effect of 2 doses of caffeine on metabolic variables and the viability of neonatal pigs with peripartum asphyxia.

Materials and Methods

Animals—Neonatal pigs (n = 180) born to 40 York-shire-Landrace sows at a commercial swine farm in the central area of Mexico were used in the study. Sows were in their second to fifth gestation and weighed between 172 and 284 kg. The sows were housed in farrowing crates in a room maintained at a temperature of 23 ± 2°C. None of the births were induced by administration of prostaglandin F or other uterotonic treatments. No medical care was offered to the neonatal pigs during the first few minutes after birth, and asphyxiated pigs were not resuscitated.

The experimental protocol of the study was approved by the Doctoral Commission of Biological Sciences of the Universidad Autónoma Metropolitana-Iztapalapa-Xochimilco, Mexico City Mexico. The study was performed in accordance with established national guidelines11 and in accordance with guidelines for the ethical use of animals in experimental studies.12

Classification of neonatal pigs—Researchers recorded the time of birth, birth weight, sex, and morphology of the umbilical cord immediately after birth of each pig. Vitality was measured by use of a vitality scale described in 1 study13 and modified as described in another study.4 Five categories were evaluated. Cardiac frequency was determined by use of a stethoscope and classified as < 110, 121 to 160, and > 161 beats/min. The interval between birth and the first respiration (the point at which thoracic movements were observed in the pig accompanied by the exhalation of air) was classified as < 60 seconds, 16 to 59 seconds, and > 15 seconds. Skin color was classified as pale, cyanotic, or pink. The interval between birth and standing on all 4 limbs was classified as > 5 minutes, 1 to 5 minutes, and < 1 minute. Meconium staining of the skin was classified as severe, mild, or none. A score of 0 (worst) to 2 (best) was assigned for each of these categories and used to obtain an overall vitality score between 0 and 10 for each neonatal pig.

The neonatal pigs were assigned to 2 groups on the basis of results for the vitality scale. Ninety neonatal pigs with a score of ≥ 8 on the vitality scale and that had an umbilical cord that was not edematous, hemorrhagic, or torn were considered to have passed the vitality assessment (group P). The other 90 neonatal pigs had a score of ≤ 5 on the vitality scale and had an edematous, hemorrhagic, or torn umbilical cord; these pigs were considered to have failed the vitality assessment (group F).

Experimental procedures—Within each group, there were 3 subgroups of 30 pigs each. Within each group, the 3 subgroups received a placebo that consisted of an empty gelatin capsule,a gelatin capsule that contained 20 mg of caffeine,b and a gelatin capsule that contained 35 mg of caffeine,b respectively; all capsules were administered orally (0 hours).

Blood samples were collected immediately before and at 24 hours after capsule administration. Blood samples were collected via retro-orbital puncture by use of capillary tubes with 100 μL of lithium heparin. Samples were collected in < 30 seconds. Total blood glucose and lactate concentrations and pH were analyzed by use of a critical blood variables analyzer.c To evaluate energy variables of the neonatal pigs, total blood triglyceride and cholesterol concentrations were determined by use of a rapid diagnostic blood analyzer.d

After caffeine administration at time 0, each neonatal pig was weighed and then returned to the vulva region of its dam to allow it to begin the search for a teat to suckle. Subsequent body weights were obtained at 24, 48, 72, 120, 144, 168, 192, and 216 hours.

Statistical analysis—Mean ± SEM values for birth weight, body weight at 8 days after birth, and blood concentrations of glucose, lactate, cholesterol, and triglyceride were calculated for each of the 3 subgroups in groups P and E The pH values were expressed as median (range).

Data were analyzed by use of an ANOVA on a statistical programe for microcomputers14 followed by the Tukey multiple comparisons test.15 Analysis of pH was conducted by use of an ANOVA followed by the Dunn post hoc test. For all analyses, values of P ≤ 0.01 were considered significant.

Results

Triglyceride, cholesterol, glucose, and lactate concentrations for pigs in groups P and F were measured. The triglyceride concentrations at 0 hours were similar in the neonates of the 2 groups (Figure 1); however, by 24 hours after birth, those concentrations had decreased significantly in pigs of group F that received the placebo treatment. At 24 hours after birth, triglyceride concentrations increased significantly in pigs that received 20 or 35 mg of caffeine in both groups P and F compared with triglyceride concentrations at time 0. During this 24-hour period, triglyceride concentrations increased significantly in pigs that received 20 or 35 mg of caffeine, but the increase was greater in pigs that received the 35-mg dose of caffeine than in pigs that received the 20-mg dose.

No differences were detected in cholesterol concentrations between groups P and F at 0 hours (Figure 2).

Figure 1—
Figure 1—

Mean ± SEM blood concentrations of triglycerides in pigs in 2 groups that were orally administered a gelatin capsule that contained a placebo (Pia), 20 mg of caffeine, or 35 mg of caffeine immediately after birth. Time of capsule administration was designated as time 0. Neonatal pigs were assessed immediately after birth and assigned to 2 groups on the basis of results for a vitality scale (range, 0 to 10). Neonatal pigs with a score ≥ 8 and with an umbilical cord that was not edematous, hemorrhagic, or torn were considered to have passed the vitality assessment (group P [white bars]), and neonatal pigs with a score ≤ 5 and with an edematous, hemorrhagic, or torn umbilical cord were considered to have failed the vitality assessment (group F [black bars]). Values at 0 hours represent results for 90 neonata pigs, whereas values at 24 hours represent results for 30 neonatal pigs/treatment. *Within a group (ie, P or F), value differs significantly (P < 0.01; ANOVA followed by Tukey post hoc test) from the value at 0 hours. †Within a group, value differs significantly (P< 0.01; ANOVA followed by Tukey post hoc test) from the value for the group receiving 20 mg of caffeine. ‡Value differs significantly (P < 0.01; ANOVA followed by Tukey post hoc test) from the value for the corresponding treatment in group R.

Citation: American Journal of Veterinary Research 71, 10; 10.2460/ajvr.71.10.1214

Figure 2—
Figure 2—

Mean ± SEM blood concentrations of cholesterol in pigs in 2 groups that were orally administered a gelatin capsule that contained a placebo (Pla), 20 mg of caffeine, or 35 mg of caffeine immediately after birth. See Figure 1 for remainder of key.

Citation: American Journal of Veterinary Research 71, 10; 10.2460/ajvr.71.10.1214

However, at 24 hours after birth, pigs in group F that received the placebo had a lower cholesterol concentration, compared with the cholesterol concentration in the placebo-treated pigs in group P. The group F pigs treated with 35 mg of caffeine had significantly higher cholesterol concentrations at 24 hours than did the group P pigs that received the same dose of caffeine.

Lactate concentrations at 0 hours in group F were approximately 65% higher than those in group P (Figure 3). At 24 hours after birth, all pigs in groups P and F had a significant decrease in lactate concentration, although the decreases for pigs in group F treated with 20 or 35 mg of caffeine were larger (50% and 40%, respectively) than the decrease for the placebo-treated pigs in group F (34%). However, lactate concentrations for the various treatment groups for the pigs in group F were significantly higher, compared with the lactate concentrations in the corresponding treatment groups for pigs in group P.

Figure 3—
Figure 3—

Mean ± SEM blood concentrations of lactate in pigs in 2 groups that were orally administered a gelatin capsule that contained a placebo (Pia), 20 mg of caffeine, or 35 mg of caffeine immediately after birth. See Figure 1 for remainder of key.

Citation: American Journal of Veterinary Research 71, 10; 10.2460/ajvr.71.10.1214

Figure 4—
Figure 4—

Mean ± SEM blood concentrations of glucose in pigs in 2 groups that were orally administered a gelatin capsule that contained a placebo (Pia), 20 mg of caffeine, or 35 mg of caffeine immediately after birth. See Figure 1 for remainder of key

Citation: American Journal of Veterinary Research 71, 10; 10.2460/ajvr.71.10.1214

As a result of asphyxia during delivery, glucose concentrations were significantly lower in group F pigs than in group P pigs at 0 hours (49.63 mg/dL vs 68.32 mg/dL, respectively; Figure 4). This decrease was maintained at 24 hours after birth. Glucose concentrations increased significantly at 24 hours after birth for pigs in group F treated with 20 or 35 mg of caffeine (30% and 50%, respectively), whereas glucose concentration was unchanged at 24 hours after birth in group P pigs.

Comparison of blood pH at various time points revealed significant differences between the placebo-treated pigs in groups P and F at 24 hours after birth (Table 1). Moreover, pigs in group P had a significant increase in pH at 24 hours after birth. The pH for placebo-treated pigs of group F did not increase significantly between 0 and 24 hours after birth. Pigs in group F treated with 20 or 35 mg of caffeine had a significant increase at 24 hours after birth, compared with the value for the pigs in group F treated with the placebo.

Table 1—

Mean ± SE blood pH in neonatal pigs In 2 groups* that were orally administered a gelatin capsule that contained a placebo, 20 mg of caffeine, or 35 mg of caffeine Immediately after birth

GroupAt birth (0 h; n = 90 pigs)Placebo (24 h; n = 30 pigs)20 mg of caffeine (24 h;n = 30 pigs)35 mg of caffeine (24 h; n = 30 pigs)
P7.38 ± 0.40a7.46 ± 0.26b,A7.48±0.21b7.46 ± 0.26b
F7.21 ± 0.25a7.22 ± 0.40a,B7.44 ± 0.34b7.31 ± 0.36b

Time of capsule administration was designated as time 0.

Neonatal pigs were assessed immediately after birth and assigned to 2 groups on the basis of results for a vitality scale (range, 0 to 10). Ninety neonatal pigs with a score of ≥ 8 and with an umbilical cord that was not edematous, hemorrhagic, or torn were considered to have passed the vitality assessment (group P), and 90 neonatal pigs with a score of ≤ 5 and with an edematous, hemorrhagic, or torn umbilical cord were considered to have failed the vitality assessment (group F).

Within a row, values with different superscript letters differ significantly (P < 0.01; ANOVA followed by Dunn post hoc test).

Within a column, values with different superscript letters differ significantly (P ≤ 0.01; ANOVA followed by Dunn post hoc test).

Birth weight and body weight of the pigs in groups P and F at 8 days after birth were measured (Table 2). Pigs in group F had a significantly higher birth weight than did pigs in group P (1,618.0 ± 186.3 g vs 1,450.4 ± 131.2 g, respectively). At 8 days after birth, body weight of placebo-treated pigs in group F was significantly (P < 0.001) less than that of placebo-treated pigs in group P. No differences were detected in body weight at 8 days after birth between pigs in groups P and F that were treated with 20 mg of caffeine. In contrast, the body weight at 8 days after birth in pigs of group F treated with 35 mg of caffeine was approximately 8% lower than that of the corresponding pigs in group P At 8 days after birth, pigs in group F treated with 35 mg of caffeine had significantly less weight gain than did placebo-treated pigs in both groups P and E.

Table 2—

Mean ± SEM birth weight and body weight at 8 days after birth In neonatal pigs In 2 groups* that were orally administered a gelatin capsule that contained a placebo, 20 mg of caffeine, or 35 mg of caffeine Immediately after birth.

VariablePlacebo20 mg of caffeine35 mg of caffeine
Group P (n = 27 pigs)Group F (in = 28 pigs)Group P (in = 30 pigs)Group F (in = 29 pigs)Group P (in = 30 pigs)Group F (in = 30 pigs)
Birth weight (g)1,456.7 ± 134.3a1,625.7 ± 195.0b1,445.3 ± 134.7a1,601.0 ±208.7b1,449.3 ±124.6C1,629.3 ± 155.2b
Body weight at 8 days after birth (g)2,577.0 ± 213.5a2,206.4 ± 204.8b2,630.7 ± 206.4a,c2,648.7 ± 299.8a,c3,029.0 ± 268.9c2,785.0 ± 312.8c

Within a row, values with different superscript letters differ significantly (P ≤ 0.01; ANOVA followed by Tukey post hoc test).

See Table 1 for remainder of key.

Discussion

In the study reported here, we determined that the administration of caffeine leads to improvements in the acid-base balance and metabolic status of neonatal pigs with poor vitality because of asphyxia during birth. Hypoxia, hypercarbia, and metabolic acidosis secondary to anaerobic metabolism are essential features of asphyxia. Evaluation of these variables and biophysical assessment by use of a vitality scale are used to reflect the severity of intrapartum asphyxia in animals.4,6,7 We observed that the pigs in group F that did not receive caffeine did not have increases in concentrations of circulating triglycerides after birth. In fact, those concentrations actually decreased significantly during the succeeding 24 hours. However, the administration of 20 or 35 mg of caffeine to neonatal pigs in groups P and F resulted in significant increases in the concentrations of circulating triglycerides at 24 hours after birth. The importance of triglycerides at birth is reflected in the mortality rate for neonatal pigs, which has been associated with a diminished energy balance during the first few hours after birth such that they are unable to increase their body temperature and thus become immobile and unable to reach a teat of the dam to obtain nutrients.16 Clearly, this also increases the probability that they will die as a result of crushing by the dam.

The decrease in triglyceride concentrations in the pigs in group F could have been attributable to the relation between the nucleoside adenosine and the intrapartum asphyxia process. An increase in concentrations of adenosine during the processes of oxygen restriction has been reported.17 An increase in the concentration of this nucleoside causes inhibition of catecholamines18,19 required for the process of breaking down the fatty acids of adipose tissue,20 thus restricting this particular method for obtaining energy However, caffeine is an antagonist of adenosine receptors21,22 and may have inhibited the effects of adenosine in the group F pigs that received 20 or 35 mg of caffeine and were thus able to obtain energy from triglycerides. Mobilization of fatty acids as a result of the effects of caffeine, which were detected in the study reported here, may provide neonatal pigs with a source of energy at birth that increases their probability of survival by making it possible for them to obtain colostrum and milk during the important early postpartum period. The lipolytic effect of caffeine has been evaluated in in vitro studies20,23,24 of rat cells; however, to our knowledge, triglyceride concentrations in neonatal pigs with and without evidence of in utero asphyxia have not been characterized previously, and the effects of caffeine on the metabolism of lipids in neonatal pigs have not been evaluated.

It should be mentioned that we are not aware of any previous studies related to determination of cholesterol concentrations in neonatal pigs in production breeds.

In our study, pigs in group F had reduced concentrations of cholesterol at 24 hours after birth, compared with concentrations of cholesterol at birth, but the cholesterol concentrations of the pigs in group F that were treated with 20 or 35 mg of caffeine increased significantly in the 24 hours after birth, with the greatest change in the pigs that received 35 mg of caffeine. The effects of caffeine to increase the synthesis of cholesterol could have been related indirectly to the increase in triglyceride concentrations that was detected coincidentally in those pigs in group F that received caffeine, which had higher concentrations of cholesterol. This result may be explained by an increase in the breakdown of triglycerides, which results in formation of A-CoA. However, when A-CoA accumulates to amounts beyond the oxidation capacity, it can lead to the formation of 3-hydroxy-3-methylglutaryl CoA and, subsequently through a chain reaction, to the synthesis of cholesterol.8,25 However, in contrast, the lack of de novo synthesis of cholesterol through an increase in amounts of A-CoA that results from an increase in lipolysis may explain the significant decrease in triglyceride concentrations and the resulting decrease in cholesterol concentrations at 24 hours after birth in the group F pigs that did not receive caffeine.

In all group P pigs, the lactate concentration and pH at birth were within the limits (mean ± SD lactate concentration, 32 ± 2 mg/dL to 49 ± 6 mg/dL; pH, 7.17 to 7.29) reported7 by other researchers for neonatal pigs that had no problems at birth. Moreover, at 24 hours after birth, the lactate concentrations in pigs of group P were similar to those reported in another study5 for pigs at 24 hours after birth that had no evidence of intrapartum asphyxia (< 40 mg/dL), which suggests the natural onset of activity of the respiratory nervous center during the first few hours after birth.

In the present study, blood samples were collected before the neonatal pigs began spontaneous respiration. For this reason, the pigs in group F had low blood lactate concentrations and a high blood pH. The lactate concentrations at birth in the pigs in group F were typically 50% higher than those for pigs in group P and were similar to those reported4 for neonatal pigs that had severe asphyxia during birth (86.3 ± 28.4 mg/dL). The elevated lactate concentrations may have been the result of a decrease in the supply of oxygen to the tissues, which leads to cellular hypoxemia and invariably to the generation of high lactate concentrations and a decrease in blood pH.26,27 These abnormal values are secondary to a poorly compensated acid-base disturbance or a combination of metabolic and respiratory alterations that results in an imbalance toward alkalosis or acidosis.5 The increase in lactate concentrations and the decrease in blood pH can be reversed. In 1 study6 investigators detected significant (P < 0.005) decreases in lactate concentration and increases in pH in neonatal pigs that were administered 40% oxygen. However, it is not feasible for practitioners to administer oxygen as a means of stabilizing neonatal pigs with signs of intrapartum asphyxia. In the present study, pigs treated with caffeine were more efficient at reducing the blood lactate concentration at 24 hours after birth than were placebo-treated pigs. This effect of caffeine represents a useful marker for determining the prognosis of survival in neonates with intrapartum asphyxia and hyperlactatemia, given that investigators in another study28 determined that pigs with high lactate concentrations at birth are likely to die within 3 weeks after birth.

In other studies,4,7 high blood glucose concentrations at birth have been detected in pigs with asphyxia,8 a phenomenon explained by the stimulation of liver glycogenolysis secondary to intrapartum asphyxia.7 However, in cases of prolonged asphyxia, a depletion of the reserves of hepatic glycogen to the point of hypo-glycemia would be expected, which would explain the lower blood glucose concentrations in group F pigs as compared with group P pigs at 0 and 24 hours. Nevertheless, this process was compensated for at 24 hours in group P and F pigs treated with caffeine, which induced a significant increase in blood glucose concentrations that reflected a normalization of the metabolic alterations secondary to the stress resulting from asphyxia at birth. Caffeine has been used in the care and treatment of preterm human neonates with episodes of apnea29,30 because of the direct effect it exerts on the CNS by increasing the sensitivity of the respiratory nervous center to carbon dioxide such that the ventilatory response also is augmented.29 Interestingly, during the 24-hour period after birth, the elevated lactate concentrations in the pigs in group F were also decreased. Lactate in the gluconeogenic pathway31 can be reconverted into glucose to obtain energy, thus contributing to the increase in glucose detected in the study reported here.

In other experiments conducted under controlled conditions,5 investigators found that neonatal pigs with intrapartum asphyxia that have a failing score when assessed by use of a vitality scale have a significantly lower body weight at 5 days after birth, compared with the body weight of pigs that did not have intrapartum asphyxia and therefore had a passing score when assessed by use of a vitality scale (mean ± SD, 1,648 ± 227 g vs 1,852 ± 100 g, respectively). Those results are similar to the ones in the present study in which the pigs in group F that did not receive caffeine had a lower body weight at 8 days after birth than did the placebo-treated pigs in group P However, the greatest effect of caffeine in the study was on the body weight at 8 days after birth in pigs of group F that were treated with 35 mg of caffeine, which had had a significantly higher body weight than that for placebo-treated pigs in group E In fact, the weight gain in pigs of group F that were treated with 35 mg of caffeine was more than that attained by placebo-treated pigs of group P. This result may have been a consequence of the improvements in the metabolic variables detected during the first few hours after birth, which probably allowed those pigs to increase their food consumption. In preterm neonatal humans with breathing difficulties, there is a slight decrease in body weight (< 16 g) 1 week after administration of caffeine22; however, we detected a different effect in the present study in which administration of caffeine to neonatal pigs of group F led to a significant increase in body weight at 8 days after birth.

Metabolic improvements during the first few days after birth in pigs that had intrapartum asphyxia determine their capacity to adapt to extrauterine life and their subsequent survival.2 Analysis of the findings of the study reported here suggested a marked acceleration of metabolic improvement during the first 24 hours after birth as a result of oral administration of caffeine in neonatal pigs with oxygen restriction during birth (ie, asphyxia, which was reflected in a failing grade on the vitality scale). However, the administration of caffeine was not related to the mortality rate of the pigs that died before the conclusion of the study because only 1 pig in group F that was treated with 20 mg of caffeine died, whereas the placebo-treated pigs in group F had a similar mortality rate.

Results of the present study indicated that caffeine administered at birth to pigs that have a low vitality score associated with intrapartum asphyxia causes hyperglycemia, an increase in cholesterol and triglyceride concentrations, a decrease in lactate concentrations, and an increase in blood pH at 24 hours after birth, all of which indicate that this treatment quickly reverses the metabolic acidosis that causes low pH and the accumulation of lactate that is characteristic of pigs with oxygen restriction during birth. In this study, administration of 20 or 35 mg of caffeine to neonatal pigs improved weight gain by approximately 20% or 26%, respectively, which indicated that it is possible to reverse the metabolic alterations by administering caffeine during the first few hours after birth to pigs that have oxygen restriction in utero and to thus increase the probability of survival and improve the prognosis for those pigs.

Abbreviations

A-CoA

Acetyl-coenzyme A

a.

Randall GCB. Pig mortality in the immediate perinatal period (abstr). J Am Vet Med Assoc 1973;163:1181.

b.

Cafeína, Future Foods SA de CV, Mexico City, Mexico.

c.

GEM Premier 3000, Instrumentation Laboratory Diagnostics SA de CV, Mexico City Mexico.

d.

MCA equipment, Roche, Germany.

e.

SAS, version 9.0, SAS Institute Inc, Cary NC.

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  • 18

    Benowitz NL. Clinical pharmacology of caffeine. Annu Rev Med 1990;41:277288.

  • 19

    Donovan JLDeVane CL. A primer on caffeine pharmacology and its drug interactions in clinical psychopharmacology Psychopharmacol Bull 2001;35:3048.

    • Search Google Scholar
    • Export Citation
  • 20

    Morimoto CKameda KTsujita T, et al. Relationships between lipolysis induced by various lipolytic agents and hormone-sensitive lipase in rat fat cells. J Lipid Res 2001;42:120127.

    • Crossref
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    • Export Citation
  • 21

    Carter AJO'Connor WTCarter MJ et al. Caffeine enhances acetylcholine release in the hippocampus in vivo by a selective interaction with adenosine A; receptors. J Pharmacol Exp Ther 1995;273:637642.

    • Search Google Scholar
    • Export Citation
  • 22

    Schmidt BRoberts RSDavis P et al. Caffeine therapy for apnea of prematurity. N Engl J Med 2006;354:21122121.

  • 23

    Kuo JFDe Renzo EC. A comparison of the effects of lipolytic and antilipolytic agents on adenosine 3′ 5′-monophosphate levels in adipose cells as determined by prior labelling with adenine-814. J Biol Chem 1969;244:22522260.

    • Crossref
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    Bray GAMothon SCohen AS. Mobilization of fatty acid in genetically obese rats. J Lipid Res 1970;11:517521.

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    Mathews CKvan Holde KEAhern KG. Chapter 19. In: Mathews CKvan Holde KEAhern KG, eds. Bioquìmica. 3rd ed. Madrid, Spain: Addison Wesley, 2002;714, 726, 770771.

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  • 26

    Deshpande SA Platt MPW. Association between blood lactate and acid-base status and mortality in ventilated babies. Arch Dis Child Fetal Neonatal Ed 1997;76:F15F20.

    • Crossref
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    • Export Citation
  • 27

    Da Silva SHennebert NDenis R, et al. Clinical value of a single postnatal lactate measurement after intrapartum asphyxia. Acta Paediatr 2000;89:320323.

    • Crossref
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    • Export Citation
  • 28

    English PRWilkinson V. Management of the sow and litter in late pregnancy and lactation in relation to piglet survival and growth. In: Cole DJAFoxcroft GR eds. Control of pig reproduction. London: Butterworths, 1982;479506.

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    • Export Citation
  • 29

    Chardon KBach VTelliez F et al. Effect of caffeine on peripheral chemoreceptor activity in premature neonates interaction with sleep stages. J Appl Physiol 2004;96:21612166.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30

    Hoecker CNelle MBeedgen B et al. Effects of a divided high loading dose of caffeine on circulatory variables in preterm infants. Arch Dis Child Fetal Neonatal Ed 2006;91:F61F64.

    • Search Google Scholar
    • Export Citation
  • 31

    Warnes DMSeamark RFBallard FJ. The appearance of gluconeogenesis at birth in sheep. Activation of the pathway associated with blood oxygenation. Biochem J 1977;162:627634.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Figure 1—

    Mean ± SEM blood concentrations of triglycerides in pigs in 2 groups that were orally administered a gelatin capsule that contained a placebo (Pia), 20 mg of caffeine, or 35 mg of caffeine immediately after birth. Time of capsule administration was designated as time 0. Neonatal pigs were assessed immediately after birth and assigned to 2 groups on the basis of results for a vitality scale (range, 0 to 10). Neonatal pigs with a score ≥ 8 and with an umbilical cord that was not edematous, hemorrhagic, or torn were considered to have passed the vitality assessment (group P [white bars]), and neonatal pigs with a score ≤ 5 and with an edematous, hemorrhagic, or torn umbilical cord were considered to have failed the vitality assessment (group F [black bars]). Values at 0 hours represent results for 90 neonata pigs, whereas values at 24 hours represent results for 30 neonatal pigs/treatment. *Within a group (ie, P or F), value differs significantly (P < 0.01; ANOVA followed by Tukey post hoc test) from the value at 0 hours. †Within a group, value differs significantly (P< 0.01; ANOVA followed by Tukey post hoc test) from the value for the group receiving 20 mg of caffeine. ‡Value differs significantly (P < 0.01; ANOVA followed by Tukey post hoc test) from the value for the corresponding treatment in group R.

  • Figure 2—

    Mean ± SEM blood concentrations of cholesterol in pigs in 2 groups that were orally administered a gelatin capsule that contained a placebo (Pla), 20 mg of caffeine, or 35 mg of caffeine immediately after birth. See Figure 1 for remainder of key.

  • Figure 3—

    Mean ± SEM blood concentrations of lactate in pigs in 2 groups that were orally administered a gelatin capsule that contained a placebo (Pia), 20 mg of caffeine, or 35 mg of caffeine immediately after birth. See Figure 1 for remainder of key.

  • Figure 4—

    Mean ± SEM blood concentrations of glucose in pigs in 2 groups that were orally administered a gelatin capsule that contained a placebo (Pia), 20 mg of caffeine, or 35 mg of caffeine immediately after birth. See Figure 1 for remainder of key

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  • 17

    Feldman RSMeyer JSQuenzer LENicotine and caffeine . In:Feldman RSMeyer JSQuenzer LF, eds. Principles of neuropsychopharmacology. Sunderland, Mass: Sinaver Associates Inc, 1997;615623.

    • Search Google Scholar
    • Export Citation
  • 18

    Benowitz NL. Clinical pharmacology of caffeine. Annu Rev Med 1990;41:277288.

  • 19

    Donovan JLDeVane CL. A primer on caffeine pharmacology and its drug interactions in clinical psychopharmacology Psychopharmacol Bull 2001;35:3048.

    • Search Google Scholar
    • Export Citation
  • 20

    Morimoto CKameda KTsujita T, et al. Relationships between lipolysis induced by various lipolytic agents and hormone-sensitive lipase in rat fat cells. J Lipid Res 2001;42:120127.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21

    Carter AJO'Connor WTCarter MJ et al. Caffeine enhances acetylcholine release in the hippocampus in vivo by a selective interaction with adenosine A; receptors. J Pharmacol Exp Ther 1995;273:637642.

    • Search Google Scholar
    • Export Citation
  • 22

    Schmidt BRoberts RSDavis P et al. Caffeine therapy for apnea of prematurity. N Engl J Med 2006;354:21122121.

  • 23

    Kuo JFDe Renzo EC. A comparison of the effects of lipolytic and antilipolytic agents on adenosine 3′ 5′-monophosphate levels in adipose cells as determined by prior labelling with adenine-814. J Biol Chem 1969;244:22522260.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24

    Bray GAMothon SCohen AS. Mobilization of fatty acid in genetically obese rats. J Lipid Res 1970;11:517521.

  • 25

    Mathews CKvan Holde KEAhern KG. Chapter 19. In: Mathews CKvan Holde KEAhern KG, eds. Bioquìmica. 3rd ed. Madrid, Spain: Addison Wesley, 2002;714, 726, 770771.

    • Search Google Scholar
    • Export Citation
  • 26

    Deshpande SA Platt MPW. Association between blood lactate and acid-base status and mortality in ventilated babies. Arch Dis Child Fetal Neonatal Ed 1997;76:F15F20.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27

    Da Silva SHennebert NDenis R, et al. Clinical value of a single postnatal lactate measurement after intrapartum asphyxia. Acta Paediatr 2000;89:320323.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    English PRWilkinson V. Management of the sow and litter in late pregnancy and lactation in relation to piglet survival and growth. In: Cole DJAFoxcroft GR eds. Control of pig reproduction. London: Butterworths, 1982;479506.

    • Search Google Scholar
    • Export Citation
  • 29

    Chardon KBach VTelliez F et al. Effect of caffeine on peripheral chemoreceptor activity in premature neonates interaction with sleep stages. J Appl Physiol 2004;96:21612166.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30

    Hoecker CNelle MBeedgen B et al. Effects of a divided high loading dose of caffeine on circulatory variables in preterm infants. Arch Dis Child Fetal Neonatal Ed 2006;91:F61F64.

    • Search Google Scholar
    • Export Citation
  • 31

    Warnes DMSeamark RFBallard FJ. The appearance of gluconeogenesis at birth in sheep. Activation of the pathway associated with blood oxygenation. Biochem J 1977;162:627634.

    • Crossref
    • Search Google Scholar
    • Export Citation

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