Eur J Appl Physiol (1984) 53:274-281 European Journal of

Applied Physiology and Occupational Physiology �9 Springer-Verlag 1984

Cardiovascular changes during whole body hyperthermia treatment of advanced malignancy

N. S. Faithfuil 1, H. S. Reinhold z, A. P. van den Berg 2, G. C. van Rhoon 2, J. van der Zee 2, and J. L. Wike-Hooley 2

i Department of Experimental Anaesthesia, Erasmus University Rotterdam, P.O. Box 1738, 3000 DR Rotterdam 2 Department of Experimental Radiotherapy, Rotterdam Radiotherapeutic Institute, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands

Summary. Cardiovascular studies were carried out on patients subjected to whole body hyperthermia treatment for advanced malignancy in order to assess the magnitude of the changes occurring and the degree of strain imposed on the system. The subjects, who were anaesthetised with a nitrous oxide/oxygen and relaxant sequence, were heated in a modified Siemens hyperthermia cabin and maintained at a body temperature of 41.8 ~ C for 2 h. The results of 30 treatments are presented. Large increases in cardiac output and heart rate were accompanied by large decreases in peripheral resistance in both the systemic and pulmonary vascular beds. The pulmonary arterial pressure rose whereas that in the systemic circulation fell. This caused right ventricular work to increase proportionately more than left ventricular work. Care should be exercised when subjecting patients with limited right ventricular function to this treat- merit.

Key words: Hyperthermia - Cardiovascular changes - Human - Malignancy treatment

Introduction

Following observations by Busch (1866) on the spontaneous disappearance of a histologically proven sarcoma following high fever in association with erysipelas, Coley (1893) used hyperthermia, induced by bacterial toxins, in cases of advanced malignancy. In recent years, a number of investigators including Barlogie et al. (1979); Greenlaw et al. (1980); Pettigrew et al. (1974a); Pettigrew and Ludgate (1977); Ostrow et al. (1981); Versteegh et al. (1981)

Offprint requests to: N. S. Faithful1, Department of Anaesthesia, Division of Experimental Anaesthesia, Erasmus University, 3000 DR Rotterdam, The Netherlands This work was supported by K. W. F, Grant: EUR 77-4

have employed whole body hyperthermia alone. Barlogie et al. (1979); Bull et al. (1979); Larkin et al. (1977); Moricca et al. (1979); Ostrow et al. (1981); Parks et al. (1979); Pettigrew and Ludgate (1977) have combined hyperthermia with chemotherapy and Blair and Levin (1977); Pettigrew and Ludgate (1977); Reinhold et al. (1980) have used radiotherapy in combination with whole body hyperthermia.

A number of different heating methods have been employed. Blair and Levin (1977); Greenlaw et al. (1980); Mackenzie et al. (1975) and Pettigrew and Ludgate (1977) used hot wax. Water circulating suits have been employed by Bull et al. (1979); Bynum et al. (1978) and Ostrow et al. (1981) and water circulating mattresses by Barlogie et al. (1979) and Larkin et al. (1977). Pomp (1978) and Reinhold et al. (1980) used hot air, and extracorporeal circulation was employed by Parks et al. (1979). Versteegh et al. (1981) and Loshek et al. (1981) used immersion in hot water.

Though hyperthermia treatment is generally well tolerated, Bull et al. (1979); Euler-Rolle et al. (1977); Larkin et al. (1977) and Moricca et al. (1979) have expressed concern about the degree of stress placed on the cardiovascular system and Parks et al. (1979), and Versteegh et al. (1981) have employed prophy- lactic digitalisation. Euler-Rolle et al. (1977) and Moricca et al. (1979) have used beta adrenergic blocking agents to prevent excessive rises in pulse rate and cardiac work. The purpose of the present study was to evaluate the changes taking place in the cardiovascular system due to whole body hyperther- mia and to assess the degree of strain under which the system is placed.

Methods

Patients. This study was performed during 30 consecutive whole body hyperthermia treatments. The patients, who were suffering

N. S. Faithfull et al.: Hyperthermic cardiovascular changes 275

from various types of malignancy, were all free from gross cardiorespiratory disease and, in particular, were screened to exclude the presence of intracerebral metastases. In the majority of cases hyperthermia was administered as a treatment additional to either chemotherapy or, more often, radiotherapy.

Anaesthesia and monitoring. The induction of anaesthesia was preceded by premedication with papaw,'retum (0.25 mg/kg) and hyoscine (0.005 mg/kg). Many patients were given IV diazepam (0.1- 0.2 mg/kg) during insertion of intravascular monitoring lines which were, when possible, inserted before induction of anaes- thesia.

An IV infusion was set up, usually in a vein in the dorsum of the left hand, and an intra-arterial catheter was inserted into the radial artery in the left wrist and advanced into the brachial artery. Arterial pressure was measured with a Gould Statham P231D pressure transducer connected to a Siemens E2150 pressure module, displayed on a digital display module E2160 mounted on a Syrecust 323 unit.

A 7-french gauge KMA thermodilul:ion Swan-Ganz catheter was inserted through an 8-french Cordis 501-608 catheter intro- ducer system inserted into the left subclavian vein and the catheter was advanced under pressure monitoring into the pulmonary artery. The pulmonary arterial pressure was measured with a Hewlett Packard 1280C pressure transducer and displayed on a Hewlett Packard compact monitor 78341A. This gave digital readout of pulmonary artery pressures and, after inflating the occlusion balloon, the pulmonary capillary wedge pressures. Cardiac output was measured by thermodilution using a KMA thermodilution cardiac output computer, model 3500. The injec- tare, which was injected randomly in the respiratory cycle, consisted of 10 ml of 5% dextrose solution at room tempera- ture.

Under X-ray control a 7-French 80 cm long Cordis femoro-re- nal A2 catheter was advanced through another 8-French Cordis. 501-608 catheter introducer system inserted into the left femoral vein in the groin. It was advanced until its tip lay in one of the hepatic veins. Through this catheter samples were taken of hepatic venous blood and central venous pressure was monitored on the Hewlett Packard compact monitor.

Anaesthesia was induced with an IV injection of a 1% solution of methohexitone (1 mg/kg). After muscular relaxation had been achieved using a nondepolarising relaxant, (in most cases d-tu- bocurarine was employed using an YLntravenous dosage of 0.5 mg/kg) the patient was intubated witJ~ a cuffed endotracheal tube. Intermittent positive pressure ven~:ilation was carried out using a Siemens Elema servo-ventilator 900A with a mixture of 33% oxygen and 66% nitrous oxide. The frequency of ventilation was ten inspirations per minute and the tidal volume was adjusted to obtain an end tidal expired carbon dioxide concentration of between 3 and 4%.

Every 10-15 rain the following measurements were taken: heart rate, systolic, diastolic, and mean arterial pressures, cardiac output, systolic, diastolic, and mean pulmonary artery pressures, pulmonary capillary wedge pressures, and central venous pressure. Measurements were also taken of expired carbon dioxide per- centage, and carbon dioxide minute production using a Siemens Elema carbon dioxide analyser 930. The electrocardiogram was continuously monitored.

Hyperthermia treatment. The patient was placed on a water circulating mattress with a Churchill thermo-circulator LTCM thermostatically controlled heater circulator in a Siemens hyper- thermia cabin. Thermocouples were placed in a number of positions including rectum, nasopharnyx, oesophagus, external auditory meatus, and various intramuscular and subcutaneous sites. The temperatures at these sites were measured using an Ellab digital thermometer unit DU3. The rectal temperature was taken

as "core" temperature and was used as the reference point around which heating was regulated. Evaporation of sweat from the exposed skin of the patient was prevented by covering it with thin sheets of plastic film. The head of the patient, which extended outside the cabin, was left uncovered.

The patient was heated using hot air produced in the Siemens cabin and hot water was circulated through the water mattress. Infusion fluids were warmed using a Treonic H150 haemoheater and the respiratory gases were warmed and humidified. Using this regime the patient's core temperature was raised to a plateau temperature of 41.8~ after 11/2-2 h.

The patients were maintained at plateau temperature for 2 h. At the end of this period the cabin was opened and the plastic sheeting was removed. Cooling was performed using fan ventila- tion and by circulating cold water through the mattress under the patient. Rapid cooling occurred, and when this was judged to be sufficient, the action of the non-depolarising relaxants (which were administered when necessary throughout the treatment in small IV increments of 0.1-0.2 mg/kg) were reversed using neostigmine 0.3 mg/kg preceded by atropine 0.16 mg/kg. The patients were then removed from the cabin and transferred to the intensive care unit.

Data analysis. All measurements of cardiovascular parameters mentioned above were stored in a mini computer system. The following parameters were calculated from formulas given by Kaplan (1979): left and right ventricular minute work indices, systemic and pulmonary vascular resistance indices, stroke index and systemic and pulmonary pulse pressures. Left ventricular minute work was calculated as:

(AP-PCWP) x CI x 0.014

Right ventricular work as:

(PAP-CVP) x CI x 0.014

Systemic vascular resistance was calculated as:

(AP-CVP) x 80/CI

Pulmonary vascular resistance as:

(PAP-PCWP) x 80/CI

Where: AP = Mean Arterial Pressure PAP = Mean pulmonary artery pressure PCWP = Pulmonary capillary wedge pressure CVP = Central venous pressure CI = Cardiac Index Work is expressed as kJ - rain -~ and resistance as kPa �9 1-1 �9 s.

In order to facilitate comparison, results are expressed as indices in Table 1. This indicates that the cardiac index (cardiac output per square meter body surface area) has been used in calculating derived values.

In view of the different rates of warming in different patients it was not feasible to analyse the data on a time base and therefore we opted for a fixed point marker analysis system. For each patient fixed points in the treatment were marked and measurements were thus analysed for each patient at the same stage of treatment. During cooling, which was usually very rapid, analysis was at fixed time intervals. The markers were chosen as follows: Marker 1 - immediately before induction of anaesthesia; Marker 2 - at the commencement of warming following insertion of thermocouples and covering with plastic sheeting; Marker 3 - on reaching plateau temperatures of 41.8 ~ C; Marker 4 - after 1 h at plateau; Marker 5

- at the end of plateau; Marker 6 - after 15 rain of cooling;

276 N.S. Faithfull et al,: Hyperthermic cardiovascular changes

Table 1. Cardiovascular parameters during whole body hyperthermia

Marker 1 Marker 2 Marker 3 Marker 4 (Before (Beginning (On reaching (After induction of plateau of 1 h at of warming) 41.8 ~ C) 41.8 ~ C) anaesthesia)

Marker 5 Marker 6 Marker 7 Marker 8 (At end (After (After (After of 15 min of 30 min of 45 min of plateau) cooling) cooling) cooling)

Body temperature 37.10 37.22 41.74"** 41.82"** 41.82 40.52*** 39.45*** 38.89*** (~ C) + 0.12 + 0.10 + 0.03 + 0.03 +_ 0.03 + 0.12 • 0.12 + 0.13

(20) (27) (30) (30) (30) (29) (25) (17)

Hear t rate 92.6 84.2 125.6"** 143.3"** 145.6 140.6" 136.4"** 134,0"* (beats - min -1) + 4.2 _+ 3.0 + 3.9 + 4.3 + 4.1 +_ 4.t + 3.5 + 4.3

(21) (29) (30) (30) (30) (27) (25) (15)

Systolic 15.71 14,19"* 14.57 12.72"** 12.76 12.09" 12.61 13.3 Systemic arterial + 0.63 • 0.57 • 0.61 + 0.52 +_ 0.48 -+ 0.52 • 0.44 + 0.61 Pressure (kPa) (23) (30) (30) (29) (30) (29) (28) (17)

Diastolic systemic 9.28 8.71 5.55** 6.67*** 6.67 6,17" 6.51 6.91 Arterial + 0.32 • 0.35 + 0.31 + 0.28 + 0.28 + 0.29 + 0.23 + 0.36 Pressure (kPa) (23) (30) (30) (29) (30) (29) (28) (17)

Mean systemic 11.71 10.27 10.05 8.81"** 8.73 8.19"* 8.74* 9.09 Arterial + 0.49 _+ 0.45 + 0.41 + 0.33 +_ 0.32 + 0.35 _+ 0.27 +- 0.39 Pressure (kPa) (23) (30) (30) (28) (30) (29) (28) (17)

Cardiac index 4.19 3.33** 7,50*** 7.02 7.34 6.82 6.62 6.32* (1 �9 min -1 �9 m -2) +_ 0.37 + 0.33 _+ 0.41 + 0.36 • 0.32 • 0.45 + 0.30 + 0.41

(20) (22) (22) (22) (21) (21) (22) (13)

Stroke volume 45.3 36.5** 59.2*** 49.4*** 49.8 47,9 48.4 47.7 Index (ml- m -2) + 3.2 • 3.3 + 3.0 + 3.0 + 2.6 • 2.7 _+ 2.3 • 2.1

(19) (21) (22) (22) (21) (19) (19) (11)

Pulmonary 0,79 1.08"* 1.16 1,13 1.13 1.23"* 1.47"* 1.33 Capillary wedge • 0.12 • 0.09 • 0.08 + 0.09 • 0.07 + 0.08 + 0.09 + 0.09 Pressure (kPa) (20) (26) (26) (24) (22) (26) (22) (13)

Left ventricular 0.047 0.033* 0.073*** 0.056*** 0.058 0.052 0.048 0.052 Work index _+ 0.005 _+ 0.003 + 0.006 _+ 0.004 + 0.004 + 0.006 _+ 0.003 + 0.004 (kJ . rain -1- m -2) (20) (22) (22) (21) (20) (20) (20) (11)

Central venous 0.40 0.76** 0.91 1.00 1.03 1.12" 1.57" 1.56 Pressure (kPa) +_ 0.15 • 0.16 + 0.17 + 0.20 • 0.19 _+ 0.20 + 0.22 _+ 0.19

(8) (11) (11) (11) (10) (10) (8) (4)

Systemic vascular 208,4 258.7 86.3*** 77.5* 76.8 81.5 75.7 76.8 Resistance index _+ 27.1 • 21.1 + 5.4 + 6,2 • 8.9 • 8.9 + 7.6 • 13.8 (kPa . 1-1 - s . m -2) (8) (11) (10) (10) (10) (9) (8) (4)

Systolic 3.06 2.69** 3.29*** 3.25 3.01 3.28 3.52 3.32 Pulmonary arterial • 0.26 • 0.18 + 0.23 + 0.20 + 0.21 • 0.56 + 0.16 _+ 0.36 Pressure (kPa) (18) (23) (23) (21) (17) (15) (13) (7)

Diastolic 1.15 1.31 1.40 1.41 1.39 1.59 1.67"* 1.75 Pulmonary arterial + 0,13 +_ 0.07 + 0.13 + 0.16 _+ 0.12 + 0.17 +_ 0.11 + 0.15 Pressure (kPa) (18) (23) (23) (21) (17) (15) (13) (7)

Mean pulmonary 1.88 1.83 2.19" 2.11 2.11 2.3I 2.44 2.32 Artery pressure _+ 0.15 _+ 0.11 • 0.12 + 0.16 _+ 0.07 • 0.17 + 0.17 + 0.20 (kPa) (20) (25) (25) (23) (19) (19) (16) (9)

Right ventricular 0.0054 0.0030** 0.0109"** 0.0086 0.0082 0.0081 0.0077 0.0075 Work index _+ 0.0010 • 0.0006 + 0.0015 + 0.0012 _+ 0.0008 _+ 0.0018 + 0.0012 2 0.0012 (kJ- min- ; - m -2) (8) (11) (10) (11) (10) (8) (8) (4)

Pulmonary 17.5 14.8" 8.8*** 8.7 8.9 9.1 9.0 10.5 Vascular + 2.5 + 1.9 _+ 0.9 + 1.4 + 1.2 • 1.6 • 1.6 + 2,4 Resistance index (20) (22) (22) (21) (17) (17) (15) (7) (kPa . 1-1 �9 s �9 m -2)

Means _+ SEM. Number of patients between brackets. Significance on paired t-test in comparison with previous marker point. * = P < 0.05; ** = P < 0.01; *** = P < 0.001

N. S. Faithfull et al.: Hyperthermic cardiovascular changes

Marker 7 - a f t e r 30 min of cooling; Marker 8 - a f t e r 45 min of cooling.

Means _+ 1 S E M were calculated for every single marker point. Statistical significance of difference between values at two marker points were tested using Student's t-test (two-sided). To exclude patient variance a paired t-test was used. A'P' value < 0.05 was chosen as the lowest level of significance.

Results

A number of the measured cardiovascular param- eters are presented in Table 1. Graphical presenta- tion of the principal changes in the systemic circu- lation is shown in Fig. 1 and those of the pulmonary circulation in Fig. 2.

The start of the warming period (marker 2) is usually between 45 and 60 min after the induction of anaesthesia. During this period a reduction in cardiac index and stroke index occurs. In addition, mean arterial pressure decreases slightly and there is a fall in the left ventricular work index. The pulmonary vascular resistance has fallen and the right ventricular work index is also very significantly decreased.

By the time the plateau temperature of 41.8~ C has been reached (marker 3) there has been a large and highly significant increase in both cardiac index and heart rate. Because the cardiac index has

277

increased proportionally more than heart rate, a large increase in stroke index has taken place. As would be expected, there were marked decreases in both the systemic and pulmonary vascular resistances; but whereas the systemic resistance has decreased to 34 % of its value at marker 2, pulmonary resistance has decreased to only 54%. As a result, left ventricular work has increased by 118% and right ventricular work by 275%.

During the first half of the plateau period (between marker 3 and marker 4) many of the cardiovascular changes that occurred during warming continue. There is a further fall in systemic vascular resistance and a concomitant fall in mean arterial pressure. No changes occur in pulmonary vascular resistance but there are no decreases in pulmonary artery pressure. The cardiac index does not decrease and thus, whereas left ventricular work decreases to a very significant extent, there is no decrease in right ventricular work. The heart rate continues to rise and the stroke index decreases.

It is of considerable clinical interest to note that at this moment (marker 4), left ventricular work is not significantly more than it was before the induction of anaesthesia. Right ventricular work, on the other hand, is very significantly raised above the preinduc- tion values and remains so throughout the plateau phase.

700

~'~ 600 E

Fig . 1. The effects of whole body ~ so0 hyperthermia (2 h a t 41.8 ~ C) o n a number of variables in the systemic ~ 400

circulation. From top to bottom cardiac -- 300 index (C1). Left ventricular work index (LVWI) mean systemic arterial pressure ~ 2 0 0

( A P ) and Systemic vascular resistance ,00

index (SVRI). Means • 1 S E M

r Fig . 2 . The effects of whole body E

hyperthermia (2 h a t 41 .8 ~ C) o n a n u m b e r 7 of variables in the pulmonary circulation. s From top to bottom cardiac index (CI), right ventricular work index (RVWI), m e a n pulmonary artery pressure (PAP) and > pulmonary vascular resistance index (PVRI). Means _+ 1 S E M

20 0.10

I 0.08

I 0 . 0

0 . 0

-0.02-

0.04" 5

0 q | 0.016 q

t O. 008

~E O. 006 i

2 i ~ 0004 , ~ 0.002-

1 0 5 0 -

-0.012

-0.016-

~ CI

LVWl

{- . . . . . . + . . . . . . . . . . . . . { , . .

| I ~ s v m

before begin begin mid end 15 g5 (mln) anaesthesia warming plateau plateau plateau 30

cooling

5

IE 2

c -~ 0

-J

-4

6

~ Cl

RVWI

- - - | i - . . . . . 4~ . . . . . . {_ . . . . . . _E2 . ~ ' { " { PAP

~ ~ PVRI

before anaesthesia

begin begin mid end 15 05 warming plateau plateau plateau 30 {min)

cooling

278

During the second half of the plateau (marker 4 to marker 5) there are no significant changes in cardiovascular haemodynamics, but once the cooling period commences, we see the most obvious and constant change is a very significant fall in mean arterial pressure at 15 min of cooling (marker 6), followed by a significant rise at 30 rain (marker 7). Over the same period the mean pulmonary artery pressure is steadily rising, as are the pulmonary capillary wedge pressure and central venous pressure. Steady falls in cardiac index are seen during cooling with significant decreases in left ventricular work. Right ventricular work remains largely constant.

Changes in systemic and pulmonary pulse pres- sures are also presented in Table 1. In the case of the systemic system we see a fall after induction followed by a marked rise as the plateau is reached. Similar changes occur in the pulmonary circulation but, whereas by the time midplateau is reached (marker 4) there has been a very significant decrease in systemic arterial pulse pressure, the pulmonary pulse pressure does not change. Systemic arterial pulse pressures are not then significantly different from those occurring before treatment (marker 1).

Discussion

Thermal stress sufficient to raise body temperature causes considerable anxiety and patients usually require anaesthesia. Barlogie et al. (1979); Blair and Levin (1977); Larkin et al. (1977); Parks et al. (1979); Pettigrew and Ludgate (1977) and Reinhold et al. (1980) have employed general anaesthesia and Bull et al. (1979); Bynum et al. (1979) and Ostrow et al. (1981) have used a generalised sedation technique. The different techniques employed may affect the cardiovascular changes taking place, but MacKenzie et al. (1975) have commented that they obtained similar results using different anaesthetic techni- ques.

N. S. Faithfull et al.: Hyperthermic cardiovascular changes

Tachycardia during hyperthermia treatment has been widely reported. Though absolute figures given for heart rates found at plateau temperatures vary, fairly good correlation between different reports is obtained when the changes are expressed as change in the number of beats per minute per 1 ~ C rise of body temperature (beats �9 min -1 �9 ~ C-1). The heart rates reported by various authors have been calculated on this basis and are presented in Table 2 (assuming basal temperature at the beginning of warming to be 37~ if this is not stated). As pointed out by Pettigrew et al. (1974b), heart rate continues to rise after reaching plateau temperature and, where pos- sible, both maximum heart rates and those obtained at the beginning of plateau are presented. Both Pettigrew et al. (1974) and MacKenzie et al. (1975) have pointed out that stable narcosis is necessary for a constant heart rate - we would agree.

Systemic arterial pressure changes are variable. Dubois et al. (1980); Larkin et al. (1977); Barlogie et al. (1979); Lees et al. (1980) and Kim et al. (1979) noted decreased pressure whereas Pettigrew et al. (1974b) and Euler-Rolle et al. (1977) noted increased pressures. Moricca et al. (1979); Ostrow et al. (1981) and Bynum et al. (1978) found little change. Many authors have described a rise in pulse pressure during warming - presumably this is caused by the gross vasodilation that is occurring. The resulting mean arterial pressures are then due to the overall balance between the increased cadiac output and the decreased peripheral resistance that occurs. Surpris- ingly, the literature on whole body hyperthermia treatment contains very little comment on changes in cardiac output. Parks et al. (1979) only mention that cardiac output was always increased averaging 10.81/minute in the 14 determinations made. In patients 'having marginal cardiac function' they measured pulmonary capillary wedge pressures and comment that they were 'little affected'. As no details of systemic pressures were given it is impossible to calculate the systemic resistance or left ventricular

Table 2. Reported values of heart rate changes during whole body hyperthermia treatment

Authors Mean heart rate Plateau at start temperature of warming

Mean heart rate change at beginning of plateau in beats - min -1 �9 ~ -1

Mean maximum heart rate change during plateau in beats �9 min -1 - ~ -1

Barlogie et al. (1979) 91 42~ Moricca et al. (1977) Not stated 41.8~ Ostrow et al. (1981) 105 41.8~ Kim et al. (1979) 87.6 41.5~ Larkin et al. (1977) 90 42~ Pettigrew et al. (1974 b) Not stated 42~ Bynum et al. (1976) 96 41.8~ Present authors 92.6 41.8 o C

8.5 12.0 9.2

8.1 10.0 11.5 11.9 14.4 11.0 14.0 12.8

N. S. Faithfull et al.: Hyperthermic cardiovascular changes 279

work from these figures. Kim et al. (1979) give figures indicating cardiac indices increasing on average by 72% during warming to 41.5 ~ C; our own figures indicate a 140% rise up to 41.8 ~ C which remains the same during the plateau. The lower figures from Kim's group may well be attributable to the depres- sant effect of the continuous infusion of thiopentone and fentanyl that they used. In another publication from the same group of investigators (Bull et al. 1979), in which the patients received either a 'low dose' infusion of ketamine or a similar thiopen- tone/fentanyl mixture, the cardiac index rose by 118% - from the figures of Lees et al. (1980) we have calculated that left ventricular work increases and systemic vascular resistance decreases by 25% and 51% respectively.

It should be noted at this point that when we refer to percentage changes in our own results, we are referring to mean paired percentages. Hence the values given may vary slightly from those that the reader may calculate using the figures given in Table 1.

The filling pressure of the right ventricle (the central venous pressure) has been fairly widely reported but published results are variable. Pettigrew et al. (1974b) comment that a rise of 0 .67-1 .3 kPa in central venous pressure occurs on warming - values then return to prewarming levels once hyperthermia is established. Lees et al. (1980) noted an average decrease of central venous pressure of 0.35 kPa, whereas Moricca et al. (1979) noticed no significant changes. In our own patients the only significant changes that took place occurred during cooling. Both Pettigrew and Ludgate (1977) and Mackenzie et al. (1977) comment that central venous pressure is not a good index of the need for fluid replacement - this accords with our own experiences.

Pulmonary arterial pressure changes have not been widely reported. Parks et al. (1979) noted that the pressures were little affected, but Lees et al. (1979) reported an average rise in mean pulmonary arterial pressure of 1.3% - we assume this to be non-significant. This publication is the only one available to us from which we can make calculations of right ventricular work and pulmonary vascular resistance. From the available figures we conclude that their patients experienced an average rise in right ventricular work of 110% and a fall in pulmonary vascular resistance of 7% - this compares with our own results of 215% and 50% respectively.

Very few authors have commented on changes occurring during the cooling period following whole body hyperthermia. Bynum et al. (1978) show figures demonstrating no changes in mean arterial pressure I/2 h after cooling had started. The cooling rate of their subjects was 2.7~ (rectal) over the 1st 1/2 h,

which corresponds quite well with our rate of 2.4 ~ C (pulmonary artery) over the same period. As men- tioned above, we observed transient significant decreases in pressure in this period. This effect was noted in conscious volunteers by Rowell et al. (1969) who also commented, as we do, on increases in central venous pressure in this period. We would like to draw attention once again to the different relative amounts of work performed by the left and right ventricles during hyperthermia and reiterate that, though left ventricular work was not significantly raised above pretreatment levels during the midpla- teau phase, right ventricular work was very signifi- cantly raised at this stage. These important results, which are graphically illustrated in Fig. 3, may have considerable clinical relevance when assessing the fitness of patients to undergo whole body hyperther- mia treatment.

The question naturally arises as to why decrease in systemic vascular resistance was more than pul- monary vascular resistance. The former decreased by midplateau to 31.6% of its value at the beginning of warming whereas the latter decreased to 49,8% of its pre-warming value. These differences can account for the rise in mean pulmonary artery pressure and the proportionately greater increase of right ventricular work.

Resistance to flow through a vascular bed depends on two factors. Firstly, there is the resistance to steady flow, and secondly, the resistance to pulsatile flow (impedance). Pulmonary vascular resis-

? 42

~ 41

, 0

~ 39 38

�9 ~ 37

400 �9

,_c

~ 30o 2~ u ~

c 200 �9 m

cD_

i S 100-

\

/ / \ RVWl

. . . . . . . . . . . . . . . . . . . . . . . . . . .

before begin begin mid end 15 45 (min} anaesthesia warming plateau plateau plateau 30

cool ing

Fig. 3. The effects of whole body hyperthermia (2 h at 41.8 ~ C) on percentage changes in left ventricular work index (L VWI) repre- sented by the solid line and right ventricular work index (RVWI) respresented by the broken line. Means + 1 SEM. The 100% value is taken as being the beginning of warming. The top graph shows the mean temperature changes occurring

280 N. S. Faithfull et al.: Hyperthermic cardiovascular changes

tance defined (as in the calculated results earlier presented) as the ratio of the average pressure decrease across the pulmonary vascular bed to the average flow, is very limited in that it fails to take account of the pulsatile nature of the flow (Fo6x 1980).

The concept of vascular impedance was intro- duced by Randall and Stacy (1956) and was applied by Caro and McDonald (1981) to the pulmonary circulation. Milnor et al. (1966), in a study in dogs, have demonstrated the effect of heart rate and pulmonary blood flow on the oscillatory component of hydraulic input power. At a fixed pulse rate oscillatory power varies with the square of the flow. They demonstrated, however, that flow could be increased with less input power increase if the pulse rate increased While the stroke volume remained constant. Hence, high pulse rates may prevent excessive rises of right ventricular work in patients undergoing WBHT, and one should be wary of trying to decrease heart rate by means of beta blockers (Euler-Rolle et al. 1977; Moricca et al. 1979). From the above brief discussion it is clear that the pulsatile nature of the pulmonary vascular flow will tend to cause the increase in right ventricular work to be proportionately more than is the case in the systemic circulation. In the latter the pulsatile component of work is much less and hence steady work output predominates.

References

Barlogie B, Corry PM, Yip E, Lippman L, Johnson DA, Khalil K, Tenczynski TF, Reilly E, Lawson R, Dosik G, Rigor B, Hankenson R, Freireich EJ (1979) Total Body Hyperthermia with and without chemotherapy for advanced human neo- plasms. Cancer Res 3 : 1481-1489

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Accepted September 19, 1984