714

treatment session 11 patients showed an increase in bloodflow; in patients 12, 13, and 14 it remained unchanged.On the 3rd day of the therapeutic trial with ENS,

measurements done before sixth application of ENS showedthat blood flow had improved in 12 patients, remainedunaffected in 1, and had decreased in another, comparedwith findings after surgery. After the sixth session of ENSblood flow had increased further in 11 patients (table III).Patients treated with ENS had a significantly (p<0-01)higher blood flow after the sixth session than those receivingplacebo-ENS.

In 12 out of the 14 patients repeated ENS restoredcapillary refilling to normal and reduced oedema and stasis.In patients 11 and 14, who had a fairly high blood flow at thestart of the treatment, it had no or minor effect (table I). In 4patients (nos 1, 3, 6, 7) treatment was stopped when capillaryrefilling returned to normal and the oedema and stasis hadimproved, but the signs of ischaemia reappeared. ENStreatment was reinstituted for another week and ischaemia

disappeared at least for the duration of the trial. 8 of the 10patients treated with placebo-ENS for 7 days showed nosigns of improvement. In 2 patients capillary refillingreturned to normal. ENS was better (p<0’05) than

placebo-ENS in reducing the clinical signs of ischaemia.

Case-reportA 52-year-old woman with mammary carcinoma

underwent subcutaneous mastectomy and reconstructionwith a prosthesis. The skin overlying the breast wasreduced. On the third day after surgery there were signs ofstasis and oedema. Laser doppler flowmetry showed noblood flow in the skin of the flap or at the distal part of themamilla. At the opposite breast blood flow was 40 arbitraryunits. After 3 days of ENS there was epidermolysis of theskin flap. Furthermore, there were no signs of stasis andoedema and time for capillary refilling had fallen. Laserdoppler flowmetry showed increased blood flow (5-45arbitrary units). Treatment was continued for a week afterthe flap had healed.

Discussion

Experimental and clinical studies have shown that mostskin flaps showing no capillary refilling or no blood flow asmeasured with a laser doppler flowmeter at their distal endsbecome necrotic.18.19 In 7 of 9 patients with stasis whoreceived ENS restored capillary refilling to normal andreduced oedema and stasis. In the other 2 ENS had no

effect; interestingly, these 2 patients had a relatively highblood flow at the start of the treatment. The only side-effectencountered was an allergic skin reaction in 2 of the patientsto the adhesive tape holding the electrodes in position. 8 ofthe 10 flaps treated with placebo-ENS became necrotic.No drug has been reported to have the effect that ENS has

in increasing peripheral blood flow and preventing necrosisin ischaemic flaps. ENS is easy to apply and does notproduce unwanted side-effects. Our experiments haveshown a release of the calcitonin gene related peptide(CGRP), a very potent vasodilator, after ENS. Our findingsand earlier reports12-14 indicate that ENS should be tried inischaemic surgical flaps and possibly other ischaemic skinconditions such as leg ulcers.

This work was supported by Ake Wibergs Foundation and Riksforeningenfor Atclerforskning.

Correspondence should be addressed to T. L., Department of PhysiologyII, Karolinska Institute, S-104-01 Stockholm, Sweden.

T LUNDEBERG AND OTHERS. REFERENCES

1. Barisoni DM, Veall N Effect of thymoxamine on circulation in flaps and m denervatedskin. Lancet 1969; i. 400.

2. Holmstr&ouml;m H. Influence of repair processes on the development of bipedicle tubeflaps. Thesis, Karolinska Institutet, Stockholm, 1973

3. Jurell G, Hjemdahl P, Fredholm B. On the mechanism by which antiadrenergic drugsincrease survival or critical skin flaps. Plast Reconstr Surg 1983, 72: 518.

4. Jurell G, Kaijser L. The influence of varying pressure and duration of treatment withhyperbaric oxygen on the survival of skin flaps. Scand J Plast Reconstr Surg 1973; 7:25.

5 Kerrigan CL, Daniel RK. Critical ischemia time and the failing skin flap PlastReconstr Surg 1982, 69: 986.

6. Mes LB Improving flap survival by sustaining cell metabolism within ischemic cells. astudy using rabbits Plast Reconstr Surg 1980, 65: 56.

7. Myers MB, Cherry G Enchantment of survival in devascularized pedicles by the useof phenoxybensamine Plast Reconstr Surg 1968, 41: 254.

8. Rosenfelt MG, Mermond JJ, Amara SG, et al Production of a novel neuropeptideencoded by the calcitonin gene via tissue specific RNA processing. Nature 1983,304: 129

9. Abram SE, Asiddao CB, Reynolds AC. Increased skin temperature duringtranscutaneous electncal stimulation. Anesth Analg 1980; 59: 22.

10. Kaada B. Vasodilation induced by transcutaneous electrical nerve stimulation inperipheral ischemia (Raynaud’s phenomenon and diabetic polyneuropathy) EurHeart J 1982, 3: 303.

11 Kaada B. Mediators of cutaneous vasodilatation induced by transcutaneous nervestimulation in humans. In: Sobin A, ed. Neuronal messengers in vascular function,E. K. Femstroms Symposium, Amsterdam; Elsevier, 1987. 1-12

12. Kjartansson J, Lundeberg T, Samuelson UE, Dalsgaard C-J. Transcutaneouselectrical nerve stimulation (TENS) increases survival of ischemicmusculocutaneous flaps. Acta Physiol Scand (in press).

13. Kjartansson J, Lundeberg T, Samuelson UE, Dalsgaard C-J, Hed&eacute;n P. Calcitoningene-related peptide (CGRP) and transcutaneous electrical nerve stimulation

(TENS) increasess cutaneous blood flow in a musculocutaneous flap in the rat.Acta Physiol Scand (in press).

14. Kjartansson J, Lundeberg T Korlof B. Transcutaneous electrical nerve stimulation(TENS) in ischemic tissue. J Plast Reconstr Surg (in press)

15. Ottoson D, Lundeberg T. TENS-Transcutaneous electrical nerve stimulation

Heidelberg. Springer-Verlag, 1988.16. Bajada S, Touraine A. Transcutaneous sympathetic stimulation: effects on autonomic

nervous function Clin Exp Neurol 1982, 22: 37.17. Nilsson GE, Tenland T, &Ouml;berg PA. A new instrument of continuous measurement of

tissue blood flow by light beating spectroscopy IEEE Trans Biomed Eng 1980; 1:12.

18. H&eacute;den P, Jurell G, Amander C. Prediction of skin flap necrosis Ann Plast Surg 1986;17: 485

19 H&eacute;den PG, Hamilton R, Amander C, Jurell G. Laser doppler surveillance of thecirculation of free flaps and replanted digits. Microsurgery 1985, 6: 11

Preliminary Communication

TREATMENT OF ANISMUS IN INTRACTABLECONSTIPATION WITH BOTULINUM A TOXIN

R. I. HALLAN

J. MELLING1N. R. WOMACK

N. S. WILLIAMSD. J. WALDRON

J. F. B. MORRISON2

Surgical Unit, The London Hospital, Whitechapel, London E11BB; Public Health Laboratory Service Centre for AppliedMicrobiology and Research, Porton Down, Salisbury;1 and

University Department of Physiology, Leeds2

Summary In seven patients with anismus the striatedsphincter muscle complex was selectively

weakened by local injection of Clostridium botulinum type Atoxin. Symptom scores improved significantly andcorrelated with a significant reduction in the maximumvoluntary anal canal squeeze pressure and a significantincrease in the anorectal angle on straining. Botulinum Atoxin seems to be a promising treatment for some patientswith anismus.

INTRODUCTION

THE aetiology of intractable constipation is poorlyunderstood and its treatment is unsatisfactory and

empirical. These patients can be divided broadly into two

715

groups-those with delayed colonic transit1 and those withanismus.2-5 In anismus the anal sphincters, in particular thepuborectalis, contract inappropriately on straining and thusevacuation is attempted against a closed striated sphincter.Both groups of patients are usually managed with a

high-dose cocktail of laxatives, but resistant cases may beoffered subtotal colectomy, the results of which are

variable. Some workers have attempted to treat anismusby the surgical division of the puborectalis muscle. Twoinitial reports were encouraging,9,1O but a more recentpublication with longer follow-up showed poor results."Other workers have judged the abnormality to be in theinternal sphincter and have done anorectal myectomy withsome success.12,13 Their patients probably represent a

different group from those with anismus.Anismus is due to inappropriate muscle spasm and seems

to be a dystonic condition. Since Clostridium botulinum typeA toxin14 has been highly successful in the treatment ofdystonia elsewhere, notably in blepharospasm,"strabismus,16-18 and spasmodic torticollis,19 we have

investigated its use in patients where constipation was duemainly to anismus.

PATIENTS AND METHODS

Patients

Seven patients (median age 54 years, range 28-72) with anismusdiagnosed electromyographically (EMG) by dynamicproctographys were included in the study. The normal pattern is forthe integrated EMG activity of the puborectalis and external analsphincter to inhibit on straining. In anismus there is a failure of thenormal inhibition, or an increase of EMG activity on attempteddefaecation, and all patients exhibited this abnormality. Six patientscomplained of chronic severe constipation, with infrequent bowelactions and abdominal pain and bloating, of at least ten years’duration. None could achieve a bowel action without the regular useof laxatives and had slow transit on marker studies.1 The seventh

patient had a shorter history than the others of straining at stool andtenesmus, had practised rectal digitation daily for 1 year, and had ahistologically proven solitary rectal ulcer with normal transit.Barium enema showed no evidence of megarectum in any patient.

Injection of Toxin

The toxin was injected with the patient in the left lateral positionand sedated with intravenous pethidine and diazepam. A digitalrectal examination was performed and a unipolar EMG injectionneedle inserted through the perineal skin. The needle tip wasguided into place by a finger in the anal canal. Its position in themuscle was initially confirmed by EMG, which subsequentlyproved unnecessary. The toxin was injected into the puborectalismuscle bilaterally, close to the deep part of the external analsphincter. This site was chosen because the motor end plates aresituated in the mid to posterior part of the puborectalis muscle(unpublished observation). The patients were allowed to continuetaking laxatives as required throughout the study.

Physiological AssessmentThe patients were assessed before and 4 weeks after the injection

of toxin. Perineal position was measured according to Henry andcolleagues’ method.2O Anal canal pressure was recorded by a stationpull-through technique with a water filled micro balloon andexternal transducer.2’ Rectal sensation and compliance were

assessed by the proctometrogram:22 the pressure within a highcompliance balloon in the rectum was recorded by an externaltransducer while it was filled with water at a constant rate by anexternal pump. Anorectal angles were measured by insertion of an8-gauge Foley catheter through the anal canal and injection of 30 mlof liquid barium suspension into the rectum. Lateral radiographswere taken at rest, during maximum voluntary contraction, andduring straining. The angle was measured between the posterior

Maximum voluntary squeeze anal canal pressure (A), anorectalangle on straining (B), and total symptom score (C) in patientswith anismus before and 4 weeks after treatment with botulinumA toxin.

In (A) and (B) all seven patients are shown; in (C) the six patients who had3 ng of botulinum A toxin are shown.

wall of the rectum and the barium in the catheter within the analcanal. 21

Symptoms were assessed by a visual linear analogue scale from0-10, 0 being no symptom and 10 being the maximum level that thepatient could imagine.23 All data are presented as the mean andSEM. Statistical analysis was by the paired t-test. The study wasapproved by the ethical committee of the Tower Hamlets AreaHealth Authority.

RESULTS

The first patient was injected with 10 ng botulinum Atoxin, 5 ng into each side of the puborectalis muscle. Thisdose was chosen because the puborectalis muscle isintermediate in size between the extra-ocular andsternomastoid muscles which require 3-5 and 40 ng,respectively, for paralysis,t8.19 and we thought that the doseneeded would be proportional to the muscle mass. Thispatient initially became incontinent of solid faeces, but thisresolved completely on recovery of muscle function.

In the next three patients 1 ng of toxin did not lead to anyimprovement in symptoms, even though the squeeze

pressures were reduced. A month later a second dose of 3 ngin these three patients led to improvement of symptoms andthis dose was therefore used in the remaining patients, 1 5 ngbeing injected on each side of the muscle.

4 weeks after treatment with botulinum A toxin themaximum voluntary squeeze anal canal pressure wasreduced from 70 (SEM 13) cm H2O to 28 (5) (p = 0-02) andthe anorectal angle on straining was increased from 96&deg; (7) to124&deg; (7) (p < 0-01). The total symptom score decreased from55-8 (2-7) to 29-7 (5-9) (p = 0-002). The accompanying figureshows the data for each patient. The table shows thephysiological data and symptom scores.

Four patients had an excellent clinical outcome. They feltthat their symptoms were improved after treatment withbotulinum A toxin, and requested repeat injections once theeffect had worn off and their squeeze pressures had returnedto pretreatment values 8-10 weeks later. One patient hasnow had 5 injections.

There was one complete failure. This patient did not feelany improvement in symptoms after 2 injections and is nowawaiting subtotal colectomy. Two patients became

incontinent, and cannot be regarded as treatment successes,even though their symptoms improved. One was the patientdescribed earlier who had 10 ng of toxin; the other patient,who took 20 ’Dulcolax’ tablets twice a week to achieve bowel

evacuation, had improvement in symptoms but was unable

716

PHYSIOLOGICAL INDICES AND SYMPTOMS BEFORE AND 4 WEEKSAFTER BOTULINUM A TOXIN*

*Means (SEMs) are shown. NS = not significant (p > 0 05).

to control the resulting liquid stool. Both patients becamefully continent once their sphincters recovered. The secondpatient has just had subtotal colectomy.

DISCUSSION

Botulinum A toxin greatly improved the symptoms inmost of our patients and this improvement correlated withthe physiological assessment.

Botulinum A toxin is produced by the microorganismC botulinum, and causes botulism. It blocks acetylcholinerelease, thus weakening striated muscle, and causes death byrespiratory paralysis. It is the most deadly neurotoxinknown, with a median lethal dose of 5-15 ng/kg. Intra-muscular injection of smaller doses (3-10 ng) of the toxinproduces weakness at the site of injection.’6 Completerecovery of muscle function occurs over 6-12 weeks,dependent on the dose used.

In our patients treated with botulinum A toxin thereduction in the maximum voluntary squeeze anal canalpressures and the widening of the squeeze and straininganorectal angles shows that the toxin has successfullyweakened the striated sphincter complex, affecting both theexternal anal sphincter and puborectalis muscles. Barnes eta19 could not demonstrate changes in the anorectal angle onsurgical division of the puborectalis, which might explainwhy there was little improvement of symptoms in theirpatients. It is noteworthy that in our patients the restinganorectal angle and the perineal position did not changesignificantly, indicating that the pelvic muscles still havesufficient tone to maintain the normal relation of the pelvic

floor, provided no extra stress is placed upon them-eg,voluntary contraction or straining. The significantreduction in the basal pressure was expected since theexternal sphincter contributes 15% of the resting tone.24The reduction in the minimum perceived volume after

botulinum A toxin treatment can be explained by a reversalof the sensory accommodation of the anorectum. Beforetreatment rectal accommodation had presumably increasedso that the patient could tolerate large quantities of stoolwithin the rectum. After botulinum A toxin injection thesensory accommodation seemed to revert to normal andtherefore the patients became sensitive to smaller volumes.A major concern of the use of botulinum A toxin in the

anal sphincter is that in the longterm the accumulatedmuscle weakness may lead to faecal incontinence. However,by weakening the muscle, straining should be reduced,which should result in less pudendal nerve damage25 andhence a lower risk of neuropathy developing. Incontinencemay thus be prevented rather than initiated. The fact thatthere was no significant change in the perineal positionsupports this notion. In addition, many patients withblepharospasm have now had 20 or more toxin treatmentsover 5 years without evidence of muscle weakness on

recovery. We therefore believe that permanent muscleweakness leading to faecal incontinence is highly unlikely.The facts that the muscle weakness lasts about 8 weeks

and that repeated injections are necessary are also causes forconcern. Nonetheless, the treatment was acceptable to thepatients since they requested repeat injections once theeffect had worn off.

Symptoms were improved in all but one of our patients.We do not believe that the improvement was due to aplacebo effect since there seemed to be a dose response to thetoxin. In addition, our patients were unaware of the timecourse of the muscle weakness and the return of their

symptoms correlated with increases in the squeeze

pressures.In one patient botulinum A toxin did not relieve

symptoms, despite changes in the squeeze pressure andanorectal angles, and anismus may therefore not have beenresponsible for her symptoms. Botulinum A toxin may thusbe a useful test to distinguish the patients in whom anismusis responsible for the symptoms.

R. 1. H. was supported by a grant from the Medical Research Council.

Correspondence should be addressed to N. S. BX’.

REFERENCES

1 Hinton JM, Lennard-Jones JE, Young AC. A new method of studying transit timesusing radio-opaque markers Gut 1969, 10: 842-17.

2 Barnes PRH, Lennard-Jones JE. Balloon expulsion from the rectum in constipation ofdifferent types Gut 1985, 26: 1049-52

3 Read NW, Timms JM, Barfield LJ, Donnelly TC, Bannister JJ. Impairment ofdefecation in young women with severe constipation Gastroenterology 1986, 90:53-60

4. Preston DM, Lennard-Jones JE. Anismus in chronic constipation. Dig Dis Sci 1985;30: 413-18.

5. Womack NR, Williams NS, Holmfield JHM, Morrison JFB, Simpkins KC Newmethod for the dynamic assessment of anorectal function in constipation. Br J Surg1985; 72: 994-98.

6 Preston DM, Hawley PR, Lennard-Jones JE, Todd IP Results of colectomy forsevere constipation in women (Arbuthnot Lane’s disease) Br J Surg 1984, 71:547-52.

7 Walsh PV, Peebles-Brown DA, Watkinson G. Colectomy for slow transit

constipation. Ann R Coll Surg 1987; 67: 71-75.8 Leon SH, Krishnamurthy S, Schuffler MD Subtotal colectomy for severe idiopathic

constipation Dig Dis Sci 1987, 32: 1249-549 Bames PRH, Hawley PR, Preston DM, Lennard-Jones JE Experience of postenor

division of the puborectalis muscle m the management of chronic constipation Br JSurg 1985, 72: 475-77

717

10. Wasserman IF. Puborectalis syndrome: rectal stenosis due to anorectal spasm. Dis ColRectum 1964, 7: 87-98.

11 Wallace WC, Madden WM. Experience with partial resection of the puborectalismuscle. Dis Col Rectum 1969, 12: 196-200.

12. Martelli H, Devroede G, Arhan P, Dugay C. Mechanism of idiopathic constipation:outlet obstruction. Gastroenterology 1978; 75: 623-31.

13 Yoshioka K, Keighley MRB. Anorectal myectomy for outlet obstruction Br J Surg1987; 74: 373-76.

14. Melling J, Hambleton P, Shone CC. Clostridium botulmum toxins nature andpreparation for clinical use. Eye 1988; 2: 16-23.

15. Elston JS, Russel RWR. Effect of treatment with botulmum toxin on neurogenicblepharospasm. Br Med J 1985; 290: 1857-59.

16. Scott AB Botulinum toxin injection of eye muscles to correct strabismus. Trans Am

Ophthalmol Soc 1981; 79: 734-70.

17 Fells P. Editorial. Sausages and squints. Br J Ophthalmol 1985; 69: 71718. Elston JS, Lee JP Paralytic strabismus. the role of botulinum toxin Br J Ophthalmol

1985, 69: 891-96.19. Tsui JKC, Eisen A, Stoessl AJ, Calne S, Calne DB. Double-blind study of botulinum

toxin in spasmodic torticollis. Lancet 1986; ii: 245-4720. Henry MM, Parks AG, Swash M. The pelvic floor musculature in the descending

perineum syndrome. Br J Surg 1982; 69: 470-72.21. Womack NR, Morrison JFB, Williams NS. The role of pelvic floor denervation in the

aetiology of idiopathic faecal incontinence. Br J Surg 1985; 72: 994-9822 Varma JS, Smith AN. Reproducibility of the proctometrogram. Gut 1986; 27: 288-92.23. Scott J, Huskisson EC. Graphic representation of pain. Pain 1976, ii: 175-84.24. Frenckner B, von Euler C. Influence of pudendal block on the function of the anal

sphincters Gut 1975; 16: 482-8925. Parks AG, Porter NH, Hardcastle JD The syndrome of the descending perineum.

Proc R Soc Med 1966; 59: 477-82.

Reviews of Books

Manual of Dietetic Practice

Edited by Briony Thomas. Oxford: Blackwell Scientific. 1988.Pp 638. /;22.50. ISBN 0-632014814.

DELIBERATE exclusion or inclusion of certain foods-

dieting-has been practised by man for millennia. Foodselection has usually been based on either preference ormorality. It is not easy to understand the moral principlesbehind dieting for religious reasons, but the custom is oldand widespread. Ancient Egyptian priests were forbidden toeat fish or beans and in the New Kingdom of Egypt pork wasalso forbidden. Both Jews and Muslims avoid pork and alltheir meat must be drained of blood when the animals arekilled. However, this sense of morality, as elsewhere, has notbeen conserved across cultures, for the Masai drink bloodand the ancient Mongol horseman kept at least ten horses sothat he could drink half a pint of blood from each one everytenth day.When man was a hunter-gatherer and nourishment was

scarce, preference for different foods may have played only asmall part in dieting. Even the introduction of cerealcultivation to neolithic agriculture around 5000 BC wouldhave had little impact, since the crop was limited in nature(usually wheat, rice, or maize) and in amount. As late as 1614in Genoa, the diet in the Hospital for Incurables was largelycereal-based, with 81 % of the calories coming from thatsingle source. New commodities were considered

superfluous and therefore morally and physically suspect. Ithas been said that the attainment of the superfluous causesgreater spiritual excitement than the attainment ofnecessities. Indeed, some new commodities were seen asdangerous, and efforts were made to prevent their

distribution; Cicero forbade the eating of meat, and bothpotatoes and butter were independently accused of

harbouring leprosy.The relative wealth of Europe in the Middle Ages, both in

trade and in organised distribution, enabled her inhabitantsto consume a more varied diet than people elsewhere. Forexample, Europe consumed substantial amounts of meat by1400, in contrast to the rest of the world, which was by andlarge vegetarian. The rapid expansion of international tradeafter 1500 had a major impact on the food market. Only asingle lemon graced Henry VIII’s wedding banquet forAnne Boleyn, but within the next two centuries citrus fruitsbecame widely available and cheap. Sugar, which was a rareand expensive commodity in the Middle Ages, became thechief import to Britain about 1700, and the rise in the world

production between 1843 and 1972 from 1 to 76 million tonsreflected the change in diets throughout the world.

Medical practitioners were never slow to propose changesin diet as a cure for diseases--either including foods (such aslimes) or excluding foods (as in the Allen diet for diabetes inthe pre-insulin era) to prevent or "cure" diseases. Many ofthe therapeutic dietary measures were based on Puritanmoral principle: if it tastes good (sugar), it’s bad for you; if ittastes bad (cod liver oil), then it must be good for you.The extent to which modem medicine practises dieting as

a therapeutic measure can be quickly appreciated byglancing at Briony Thomas’s remarkable book. Clear,concise, comprehensive, and well referenced, it provides anessential source of dietetic practice at a very reasonable price.Every physician should insist that both the hospital’s libraryand the dietetic department buy a copy.

King’s College School ofMedicine and Dentistry,

London SE5 8RX R. D. G. LESLIE

Controversies in Cardiovascular Anaesthesia

Edited by Phillip Fyman and Alexander W. Gotta. Dordrecht:Kluwer. 1988. Pp 192. 39.50. ISBN 0-898389852.

THE great advances in cardiac surgery in the past thirtyyears have been accompanied by a gratifying decline in itsmortality rate, which stands at around 1 % for coronaryartery surgery in the best centres, for example. Aside fromthe more recent expansion in transplant surgery, with itspractical and ethical dilemmas, our main concern nowrelates to reducing mortality in high-risk patients,preventing morbidity (and this includes our increasingawareness of and concern about permanent brain damage),and improving long-term results. Most anaesthetists, andthey are in a better position to judge than cardiologists,would probably argue that much the most important singlefactor in determining the immediate outcome of cardiacsurgery is the skill of the surgeon, and in difficult cases theadditional factor of the quality of the intensive care

teamwork. But whilst surgical techniques in adults arelargely standardised, the choice of anaesthetic agents andintraoperative management varies widely, and we have yetto determine which current approaches are best. This

multiauthor book from the United States examines somecontroversial topics in an attractive way, through well-argued pieces and opposing viewpoints. Each chapter isaccompanied by a reasonably up-to-date bibliography. Thetopics include predominantly inhalational anaesthesiaversus a purely intravenous technique for coronary arterysurgery, temperature correction (pH-stat) versus no

temperature-correction (alpha-stat) for blood gas analysis,high blood flow with high peripheral arterial pressure versuslow blood flow with low peripheral arterial pressure during