The effects of maternal hyperthermia on maternal and fetal cardiovascular and respiratory function K. C. CEFALO, ANDRE

M.D.,

PH.D.,

E. HELLEGERS,

Washington,

D.

CAPTAIN (MC)

USN

M.D.

C.

The fetus, by virtue of its location, is faced with a problem of heat elimination. Sixteen acute pregnant ewe preparations were studied. Thermistors were inserted in the maternal abdominal aorta and the umbiiicai artery and vein. Eiectromagnetk flowmeters were applied to the umbilical and uterine arteries. Maternal hyperthermia was induced by radiant heat. The fetus maintained a temperature difference to the mother during the hyperWmia. The fetal-maternal difference decreased with increasihg maternal temperature. With a 1.5” C. to 2.0” C. rise in maternal temperature there was an increase in umbilical blood flow (36 per cent) and a decrease in umbiiiii vascular resistance (40 per cent). The fetal ark&venous temperature and 0, content diierence decreased. Maternal art+& preesure did not change but respiratory rate, cardiac output, and rate of uterine Mood flow increased. Maternal systemic vascutar resistance decreased (20 per cent). At a maternal 2.0’ C. temperature rise, maternal cardiovascular coiiapse occurred. At this point fetal-maternal temperature difference increased markedly. The umbikai circulation is not only a carrier of Oe and nutrients but is a major pathway for fetal heat exchange. The ability of the fetus to eliminate heat is another reflection of the adequacy of the uteropiacental circulation. (AM. J. OBSTET. GYNECOL. 131: 887, 1978.)

IT is COMMONLY ACCEPTED that the transfer Of materials across the placenta occurs by several mechanisms.’ The respiratory gases reach the fetus by a process of diffusion while other substances such as n-and L-leucine, iron, and calcium have been shown to cross by means of active transport.*+ The processes governing the rate of transfer are also beginning to be understood.5 For such highly diffus-

From the National Nay Instilute, and Department Georgetown University Sponsored

in part

Medical Center, Kennedy of Obst&ics and Gynecology,

by the Bureau

of Medicine

and

Surgery,United St&s Navy, ClinicalInvestigation Propam No. 7-06-953, No. 5-Rol-HD-08124-02.

and Public

Health

Service

Grant

The opinions expressed herein are solely those of the authors and are not to be construed as reflecting the opinions of the Navy Department or the Department of Defense. Received

fw

Revised

November

Accepted Reprint National 20014.

publication

December

June

3, 1977.

29, 1977. 5, 1977.

requests: R. C. Cefalo, Captain (MC), USN, Naval Medical Center. Bethesda. Marvland ,

0002-937#78/06131-0687$00.80/‘0 0 1978The

C.

V. Mosby

Co.

able substances such as antipyrine and tritiated water the rate-limiting feature is the uterine blood flow. For larger molecules such as urea and for a variety of ions such as sodium, the rate-limiting factor is the placental membrane itself.]* 5 Regardless of the mechanism of transfer, it is clear that the fetus by virtue of its location is faced with a problem of heat elimination. This must necessarily occur via the mother, and the factors which govern the process are little understood. Physically, the only routes of heat egress must be the fetal surface via the amniotic fluid or the placental circulatory interchange area. The increased perinatal mobidity and mortality rate associated with maternal-fetal infection are well known. It is not clear whether the observed increased perinatal mortality rate and morbidity are due to fetal and/or maternal infection itself or to the temperature elevation per se or secondary to maternal/fetal cardiovascular effects of hyperthermia. It is not known whether fetal mortality rate or morbidity are produced by the inability of the fetus to eliminate the heat products of metabolism. The areas investigated in this paper are the car687

688

Cefalo and Hellegers

diovascular and respiratory effects of induced thermia in the ewe and the fetus.

Julv .4m. J. Obstrt.

hyper-

Methods and material Sixteen Dorset ewes with known breeding dates were studied. Prior to surgery, the ewe was fasted for 24 hours but received water at will. No sedatives were given prior to administration of the spinal anesthesia. With the ewe standing in a portable stall, the area between the iliac crest was sheared and a local anesthetic, lidocaine hydrochloride (Xylocaine), one per cent solution, was injected into the skin and subcutaneous tissue over the lumbar 3-4 vertebral interspace. With a 20 gauge spinal needle, 2 ml. of one per cent Tetracaine hydrochloride (Pontocaine) was administered after entrance into the subdural space. The ewe was moved to the operating table where it was restrained in the extreme right lateral decubitus position. The ewe breathed room air throughout the study. The level of anesthesia was checked by response to an Allis clamp and was usually just above the level of the umbilicus. Pentobarbital sodium was given intravenously 6 mg. per kilogram as a supplement when needed. The abdomen was opened by a midline incision. After confirming the number of fetuses, the pregnant uterine horn was delivered through the abdominal incision. The placental cotyledons in the uterine horn were palpated until an area of average size cotyledons was found. In this area, on the medial surface of the horn, a 3 to 4 cm. incision was made perpendicular to the long axis of the horn. Polyvinyl catheters* (inside diameter, 1 mm.; outside diameter, 1.3 mm,) with sealed in tip thermistorst were introduced into intercotyledonary branches of umbilical arteries and veins and advanced a length of 25 cm. or when the resistance of the fetal abdominal wall was encountered, then the catheter was drawn back 8 cm. In most preparations the catheter was within 4 cm. of the abdominal wall insertion of the umbilical cord. The uterine incision and fetal membranes were closed and the catheters and thermistors were secured to the uteriie wall. The thermistor probe had a 1 mm. outside diameter. Each probe was individually calibrated by Yellow Springs Instrument Company which supplied the calibration chart. The calibration chart gave the corresponding absolute temperature for each 1 ohm. increment of thermistor resistance over a range of 1,000 to 2,999 ohm. The total temperature range was from 15” C. to 45” C. Temperature values were given in two *Bolab, Reading, Massachusetts. tHewlett-Packard Company, Rockville, Maryland.

1.3. 1978 GyKcd.

decimal places. The beads of the thermistor were processed to follow the same resistance curve over the 37” C. to 43” C. temperatures range. With a HewlettPackard thermal dilution system consisting of the thermistor probe, a model 350-15 calibrated bridge circuit, and a model 8803A low-level amplifier resistance changes which corresponded directly with temperature variation were recorded. Absolute temperature measurements made with the probe were accurate to a t0.01” C. over a temperature range 20” C. to 45” C. Temperature probes were tested prior to each experiment with a Haake constant-temperature circulator water bath.* Part of the uterus containing the fetus was then delivered through the abdominal incision. A uterine incision was made over a point between the fetal rib cage and hips to gain access to the umbilical cord near its fetal abdominal wall origin. The uterine incision was made parallel to the uterine vessels. The umbilical cord was mobilized and the loose areolar tissue around a segment of an noncatheterized umbilical artery was infiltrated with a few milliliters of a warm solution containing one cent lidocaine hydrochloride Per (Xylocaine) and 5.0 mg. of phenoxybenzamine hydrochloride (Dibenzyline). A small segment of this artery was cleared of its surrounding tissues and fitted with a cuff electromagnetic flow probe. The electrical zero of the transducer flowmeter system were repeatedly checked during the experimental period.? Through a 1.5 cm uterine incision the fetal scalp electrocardiogram electrode was attached for continuous monitoring of the fetal heart rate. The major arterial supply of the uterus is via the middle uterine artery which can be readily located in the folds of the broad ligament and traced back to a point near its origin from the internal hypogastric artery. After infiltration of the surrounding tissue with Xylocaine-Dibenzyline mixture to prevent vasospasm the artery was fitted with a cuff electromagnetic flow transducer. Electrical zeros of the transducer flowmeter system were checked repeatedly. The maternal femoral artery was isolated and catheterized with a sampling thermistor catheter. This catheter was passed until the level of the maternal aorta was reached, usually 20 to 25 cm. With the use of local anesthesia, the external jugular vein was catheterized with the Swan Ganz Row directed thermodilution catheter (either Model 93113-7F or 93- 1 l&7).$ The catheter was floated into the *Haake Instrument Co., New Rochelle, New York. tBiotronix Laboratory, Silver Spring, Maryland. *Edwards Laboratories, Santa Ana, California.

Volume Number

Table

Effects of hyperthermia

13 1 6

I. Control

preheat

values*

Parameter

Fetal PYQ (mm. Hg) PyCO, (mm. Hg) P&i, Umbilical blood flowt (ml./Kg.-min.) Maternal PA02 (mm. Hg) P,CQ (mm. Hg) pb4, Uterine blood flows (ml./Kg.-min.)

on cardiovascular

Table II. Average in preheat period.

Value

maternal

and respiratory function

cardiovascular

Parameter

21.5 47.9 7.26 108.06

+ t + ?

0.6 1.7 0.02 3.71

77.4 31.9 7.55 111.38

+ 1.7 * 0.08 z!z0.09 ‘- 3.57

(a) = Umbilical artery; y = umbilical vein; A = maternal artery. *Control values for maternal and fetal parameters represent mean f 1 S.E.M. of the avtraged values obtained at three 15 minute intervals. t Expressed as per kilogram of uterus and its contents. $Values obtained from results of electromagnetic flow probe around one umbilical arrery. pulmonary artery with the characteristic pressure tracing and measurements to locate its tip. Blood samples (1.5 ml.) were handled anaerobically in oiled glass syringes with the dead space filled with heparin(l,OOO U. per milliliter. All blood samples of the mother and fetus were obtained simultaneously. The oxygen and carbon dioxide tensions and pH were measured with Instrument Laboratory 3 13 blood gas analyzer.* Analyses were made at 39” C. and corrected to body temperature. The oxygen content was determined by the L.ex-O&on.t The Lex-Os-Con was calibrated daily with room air adjusted to the actual barometric pressure, temperature, and water vapor pressure and with a known 12 per cent Oz mixture. The uterine and abdominal incisions were approximated after placing of the catheters, the thermistors, and flow probes. Following the surgery 1,000 U. of heparin was injected intravenously into the fetus. The ewe received 10,000 U. of heparin intravenously. The surgical procedure averaged 90 minutes in duration. The experimental protocol consisted of: (1) a control period of’ 40 minutes after surgery, during which phasic and mean pressures and flows and temperatures were continuously recorded (maternal and fetal blood gases and pH analyzed every 15 minutes); (2) a thermal stress period, 50 minutes, with approximate 0.5” C. increase in maternal temperature every 15 minutes; (3) a recovery period, 40 to 50 minutes. At the end of each experiment, a hysterectomy was performed and the placental cotyledons and mem*Instrumentation Laboratory, Inc., Lexington, Massachusetts. fLexington Instruments Corp.. Waltham, Massachusetts.

689

values

Results*

Arterial pressure (mm. Hg) Cardiac output (ml./Kg.-min.) Uterine blood flow (ml./Kg.-min.)t Uterine fraction of cardiac output (?G) Total systemic vascular resistance (mm. Hg/ml./min.) mm. Hg blood pressure ml./Kg./min. cardiac output Uterine vascular resistance (mm. Hg/ml./min.) mm. Hg blood pressure ml./Kg.lmin. uterine blood flow

!)3.95 2 2.67 I LO.09 k 5.38 1 Il.38 5 3.58 Il.41 I 0.90 0.887 -+ 0.04

6.26 It- 0.748

*Figures represent mean & 1 S.E.M. of averaged readings taken in the control period after surgery has been completed. tExpressed as per kilogram of uterus and its contents, one arterv.

branes were dissected free. The individual weights of the uterus, placenta (including membranes), and fetus were recorded. The position of all catheters, thermistors, and flow probes was confirmed and recorded. Because of the ability to slowly increase and rather quickly decrease maternal temperature. the bulb radiant heat method of raising the temperature of a ew? was utilized. A radiant heat source was ohrained from two 1,000 watt quartz rod lamps.* In an attempt to make recordings at a thermal equilibrium state, measurements of the fetal-maternal temperature difference (AT F-M) and umbilical artery and vein temperature difference (AT umb. a-v) were ohserved after the temperature change had occurred and remained at tht new level for four to five minutes.

Results Preheat. umbilical arteT-vein tpmppla&lr &jference. After a 40 minute postsurgical stabilization period, the control fetal-maternal temperature difference was 0.61” t 0.05“ C. (S.E.M.). The difference was calculated from a maternal aorta blood thermistor and an umbilical artery thermistor. The mean maternal temperature was 38.96” + 0.13” C. The mean fetal temperature was 39.57” rt 0.11” C. Both maternal and fetal temperatures displayed 0.1” I 0.2” C;. variation in temperature. The mean umbilical artery-umbilical vein temperature difference was 0.15” t 0,02” CL The results presented above demonstrate that the near-term fetal lamb’s temperature as judged by the umbilical artery temperature is 0.61” ” 0.05” C. warmFetal-maternal,

*Colotrom

Industries,

Burbank,

California.

690

July 15, 197X Am. J. Obstet. Gynecol.

Cefalo and Hellegers

er than maternal aorta blood temperature in 16 nearterm pregnant ewes under the conditions of our investigation. Our results are in accord with observations of earlier investigators. 6-a The above determinations were made from averaging temperatures taken at fiveminute intervals during the 40 minute postoperative stabilization period. Cardiorespiratory parameters. During the 40 minute postoperative period of stabilization, fetal blood pressure, fetal heart rate, maternal blood pressure, and maternal heart rate were continuously recorded. At 15 minute intervals, blood samples of the mother and fetus were simultaneously obtained. Blood samples were analyzed for PO*, Pcq, pH, and OZ content. Control values are shown in Table 1. The control preheat and preheat maternal cardiovascular parameters are reported in Table II. Heat. Effects of hperthermia on maternal-fetal temperatures. At a 1 .O” C. rise in maternal temperature, the fetal-maternal temperature difference decreased from 0.61” * 0.05” C. to 0.19“ f 0.03” C. (p < 0.01). At 2.0” -+ 2.5” C. rise in maternal temperature, as well as in the recovery phase, there was marked increase in the fetal-maternal temperature difference to 1.27“ _t 0.08” C. These two periods were placed together because of the trend in widening of fetal-maternal temperature differences. The 1.27” * 0.08” C. fetal-maternal difference was statistically significantly different (p < 0.01) from the fetal-maternal temperature difference in both the control period and during the 0.5” to 1.5” C. hyperthermic period. During the entire heating period, there was a decrease in the umbilical artery-umbilical vein temperature difference from a control of 0.15” * 0.02” C. to 0.07” k 0.01” C. (p < 0.01). At the end of the recovery phase, the umbilical artery-umbilical vein temperature difference was 0.30” * 0.07“ C. This difference was statistically significant from both the control period and during the 0.5” to 1.5” C. hyperthermic period. Effects of hyperthermia on cardiovascular parameters of the fetus. UMBILICAL

BLOOD

FLOW

AND

UMBILICAL

ARTERIOVEN-

In the 16 acute preparations the mean gestational age was 135.38 with a range of 130 to 143 days. The mean fetal weight was 3.68 kilograms with a range of 2.8 to 5.0 kilograms. With a cuff electromagnetic flowmeter on a single umbilical artery, the mean pre heat single umbilical artery blood flow was 108.38 & 2.28 ml. per kilogram-minute with a range 83 to 135 ml. per kilogram-minute. A 0.5“ C. rise in maternal temperature was associated with a mean umous

02 DIFFERENCES.

bilical blood flow of 138.45 + 6.38 ml. per kilogramminute. With an increase of 1.5” C. maternal temperature, the mean umbilical blood flow was 143.68 t 6.45 ml. per kilogram-minute. At 2.0” C. maternal temperature elevation, mean umbilical blood flow was 135.60 t 10.5 ml. per kilogram-minute. At 2.5” C. rise in maternal temperature fetal blood flow decreased to 116.9 2 13.00 ml. per kilogram-minute. All values were statistically different from control values except value at 2.5” C. rise in maternal temperature. In the recovery phase in 14 preparations (in two preparations fetal death occurred in utero), the mean umbilical blood flow was 134.47 * 7.45 ml. per kilogram-minute (p < 0.01). The over-all change from the preheat control period was a 37.5 per cent increase in umbilical blood flow during the induced maternal hyperthermia. Abrams and associates6 suggested a theoretic relationship between the temperature difference of the umbilical artery and umbilical vein and the umbilical blood flow as it is reflected in the arteriovenous oxygen content relationship and blood flow. In our preparations the preheat umbilical vein-artery oxygen content difference was 2.86 2 0.09 vol. per cent. During the hyperthermia phase the oxygen content across the umbilical circulation decreased to 2.48 t 0.11 vol. per cent. In the recovery phase the O2 content difference across the umbilical circulation decreased further to 2.09 ? 0.03 vol. per cent. This recovery phase oxygen content difference is statistically different from the preheat umbilical circulation 0, content difference. There was an inverse relationship between an increased umbilical blood flow and a decreased umbilical venous-arterial oxygen difference. In the recovery phase, umbilical blood flow became significantly elevated when compared with control umbilical blood flow (p < 0.01). This occurred in association with a fall in maternal temperature but a maintenance of an elevated fetal temperature and a widened fetal-maternal temperature difference. This suggested that both umbilical temperature differences and 0, content can be affected by blood flow changes. FETAL BLOOD PRESSURE. During the entire maternal heating period, the fetal arterial blood pressure did not show any dramatic or significant change. The mean fetal arterial blood pressue during this time was 45.43 ? 1.60 mm. Hg. During the recovery phase in 14 preparations, fetal blood pressure was maintained at 44.96 2 1.64 mm. Hg. HEART RATE. In 16 preparations, the postsurgical fetal heart rate ranged from 160 to 180 beats per minute. With the earliest elevation of fetal temperature, there was a significant rise in fetal heart rate of 40 to 50

Volume

131

Effects

beats per minute. With a maternal elevation in temperature of’ 1.0” to 1.5” C. the fetal heart rate remained at 200 to 240 beats per minute. At a 2.0” to 2.5” C. rise in maternal temperature, the fetus maintained a fetal heart rate above the 240 beats per minute. At this time, marked irregularities in heart rate were noted. When there was deterioration of the fetus, as evidenced by an increase in fetal (H)+ concentration or accumulation of carbon dioxide, the fetal heart rate dropped precipitiously from 240 beats per minute to 40 to 60 beats per minute. ‘This usually occurred in the recovery phase. UMBILICAL VASCULAK RESISTANCE. The 38 per cent increase in total umbilical blood Row along with statistically nonsignificant changes in fetal arterial pressure suggested a decrease in umbilicoplacental vascular resistance associated with thermal stress. The umbilical vascular resistance (determined by the relationship of fetal arterial blood pressure X 1,000 divided by umbilical blood flow in milliliters per minute during the control period in the 16 acute preparations was 153.80 t 31.22 mm. Hg per milliliters per minute. For the entire hyperthermia phase, the mean umbilical vascular resistance decreased to 87.28 * 4.96 mm. Hg per milliliters per minute (1~ < 0.01). This represents a 43.14 per cent change in vascular resistance. EFFKTSOF

HYPERTHERMIA

ON UTERINE

CIRCULATION.

In our acute preparations under spinal anesthesia, the mean control uterine blood flow was 111.37 +: 3.56 ml. per kilogram-minute with an absolute flow of 439 t 22.5 ml per minute. This is in agreement with the one-sided mean electromagnetic probe flows of Kirschbaum. and colleagues10 of 138 -t 73 ml. per kilogram per minute and with those of Assali and colleagues of I77 ml. per kilogram-minute. During radiant light-induced hyperthermia, there was a marked decrease in uterine blood flow. The mean blood flow for the entire hyperthermic phase was 88.21 -t 4.0 ml. per kilogram-minute (p < 0.01). This represented a 20.80 per cent decrease in flow. In the recovery phase, uterine blood flow remained low at 74.28 2 6.1 ml. per kilogram-minute. At a 0.5” (:. elevation in maternal temperature, the uterine blood flow was 118.9 ? 9.11 ml. per kilogram-minute. At 1.0” C. elevation the value was 122.38 t 7.90 ml. per kilogram-minute. At 1.5” C. maternal temperature elevation there was a drop in uterine blood flow to 85.46 t 6.44 ml. per kilogramminute (p < 0.01). Not all acute preparations had a 2.5’ C. rise in maternal temperature, but in thirteen preparations the mean uterine blood flow was reduced to 53.77 2 3.12 ml. per kilogram-minute (p < 0.01). The maternal arterial blood pressure changes dur-

of hyperthermia

on cardiovascular

and respirator!)

function

691

ing the hyperthermic phase were not significant. Cardiac output displayed a biphasic responst

The effects of maternal hyperthermia on maternal and fetal cardiovascular and respiratory function.

The effects of maternal hyperthermia on maternal and fetal cardiovascular and respiratory function K. C. CEFALO, ANDRE M.D., PH.D., E. HELLEGERS,...
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