Refractory HypotensionDiagnosis and Management in Surgical Patients

LOUIS L. SMITH, M.D., and BRUCE W. BRANSON. M.D., Los Angeles

Two KINDS of circulatory collapse are seen most fre-quently in acutely ill surgical patients. One is dueto acute reduction of blood volume following lossof blood, plasma or extracellular fluid. This situa-tion is obvious and specific replacement is required.Response is prompt and recovery is the ruleproviding the cause of the circulatory collapse canbe corrected. Circulatory failure of this kind can becalled "responsive hypotension.".The other kind of circulatory collapse occurs in

surgical patients who, although they seem to havea normal blood or plasma volume, do not have ade-quate circulation. Frequently such persons becauseof the obscure nature of the vascular collapse, aregiven intravenous vasopressor agents. Their re-sponse to resuscitative efforts is sluggish, and themortality rate is high. "Refractory hypotension" isan apt term for circulatory failure of this type.

In the present discussion of the possible causesand treatment of refractory hypotension, we haveavoided the term "shock" because of confusionregarding its definition and because it is frequentlyused in the experimental laboratory to describe acirculatory collapse in which death is consideredto be inevitable. Hypotension, for the purpose ofthis discussion, will refer to those clinical conditionsin which the pulse rate is accelerated, the bloodpressure low and there is evidence of impairedperfusion of vital organs.

ETIOLOGY

The following case illustrates the problem of re-fractory hypotension in a postoperative patient.A 53-year-old Caucasian housewife entered the

hospital for elective operation on the biliary tractbecause of pain in the right upper quadrant of theabdomen. She had had jaundice, which had sub-sided without medical treatment. A cholecystogramwas reported as showing a nonfunctioning gallblad-

From the Department of Surgery, Loma Linda University School ofMedicine, and the White Memorial Hospital, Los Angeles 33.

Presented as part of a Seminar on Recent Advances in the Manage-ment of Hypovolemic Shock before the Section on General Surgery atthe 90th Annual Session of the California Medical Association, LosAngeles, April 30 to May 3, 1961.

This study was supported in part by U. S. Public Health Servicegrant No. H-4639.

* Refractory hypotension is circulatory collapseof obscure cause which occurs in surgical pa-tients who are thought to have a normal bloodvolume but in whom adequate circulation cannotbe maintained. Such patients are usually treatedempirically by the administration of intravenousvasopressor agents, and the mortality rate isrelatively high.A specific diagnosis of the underlying cause

for the refractory hypotension can be made bythorough clinical evaluation. Specific treatmentaimed at correcting the underlying cause of thevascular collapse will lower the mortality rate inthis serious type of circulatory failure.

der. At operation the gallbladder was observed tocontain many stones and there was a solitary gall-stone in the common duct, which was dilated. Theampulla of Vater would not admit a No. 3 Bakesdilator and there was a cholecystduodenal fistula.The operative procedure consisted of cholecys-

tectomy, choledocholithotomy, closure of the chole-cystduodenal fistula and transduodenal sphinctero-plasty. On the first postoperative day the patient hada temperature of 102.2° F. The pulse rate was 88and the blood pressure 120/88 mm. of mercury.The hematocrit was 44 mm. (before operation it was38mm.).On the afternoon of the first postoperative day, the

patient attempted to go to the bathroom but col-lapsed on the floor in her room. Soon afterward theblood pressu-re was unobtainable and no radial pulsecould be felt. Abdominal palpation revealed no ten-derness. The hematocrit was reported as 49 mm.Intravenous Aramine® (metaraminol) drip admin-istration was begun and the blood pressure rose to65/50 mm. Intravenous corticosteroid administra-tion (Solu-Cortef® 300 mg.) did not elevate the lowblood pressure further. On the morning of the sec-ond postoperative day the temperature rose to 103.80F., the blood pressure and the pulse became unob-tainable. The patient was digitalized with Cedi-lanid,® intravenous administration of tetracylinehydrochloride (Achromycin®) was begun and theconcentration of Aramine increased in order to re-store the blood pressure. As the response was poor,drip administration of norepinephrine was begun.The hematocrit at this time was 55 mm. The pa-

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tient's condition deteriorated rapidly and she diedon the morning of the second postoperative day.At autopsy, acute pancreatitis with extensive

retroperitoneal edema and fat necrosis was noted.There was a focal area of hemorrhage within thehead of the pancreas.

In this case, the cause of vascular collapse wasnot recognized during life and plasma volume re-placement was not carried out.The causes for hypotension in surgical care are

few. Common conditions which can produce vascu-lar collapse are: Concealed hemorrhage, cardiovas-cular catastrophe, pulmonary catastrophe, invasivesepsis, electrolyte disorder, postoperative pancrea-titis, vascular impairment of bowel, acute adrenalinsufficiency.

Concealed Hemorrhage: One of the commonestcauses for unexplained circulatory failure followingoperation is concealed hemorrhage. This diagnosisis frequently obscure in the early stages before thedevelopment of abdominal distention and flank dull-ness. Continued tachycardia or hypotension respon-sive to transfusion, a falling hematocrit or bleedingfrom drain tubes should make one suspicious of thiscomplication.

Cardiovascular Catastrophe: The cardiovascularcauses for circulatory failure are well known. Pul-monary embolism, coronary occlusion, or acutecardiac arrhythmias may be responsible for refrac-tory hypotension. In all of these disorders the bloodvolume is normal and hypotension is the result of"pump failure."Pulmonary Catastrophe: Disturbances in pulmo-

nary ventilation must be considered as possible etio-logical factors in the production of refractoryhypotension. Undiagnosed pneumothorax or airwayobstruction produce vascular collapse by asphyxia.Spreading pneumonia not only impairs pulmonaryventilation but poses the threat of blood streaminvasion by the infectious agent.

Sepsis with Blood Stream Invasion: Refractoryhypotension may also be brought about by spread-ing infection with bacteremia or septicemia. Whetherthe septic process be peritonitis, enterocolitis orpneumonia makes little difference. The acute in-flammatory process is associated with the de-velopment of inflammatory edema and subsequentreduction of the plasma volume. Additional wholeblood volume may be sequestered in congested ves-sels within the area of acute inflammation. As aresult of this inflammatory process there is a reduc-tion of the plasma volume or effective whole bloodvolume.

Electrolyte Disorders With or Without Acid-BaseChanges: Acute surgical illness is frequently asso-ciated with significant losses of electrolyte-rich body

fluids through depletion of extracellular plasma vol-ume. When these losses reach a critical point, com-pensatory mechanisms fail and circulatory collapseensues. Knowledge of the pressor effect of the so-dium ion is important in understanding the patho-logic biochemical features of hypotension. Thispressor effect is evidently lost by either hyponatre-mia or sodium deficit even though the two may notoccur together. An electrolyte disorder should beconsidered in any patient with hypotension who alsohas altered cerebration or neuromuscular irritabil-ity or muscular weakness.Acute electrolyte disorders are frequently asso-

ciated with acid-base shifts which in themselves maybe responsible for altered cardiovascular function.Abnormal breathing or a change in respiratory rateis indicative of acid-base disorders. The usual acid-base change in patients with refractory hypotensionis a metabolic acidosis, frequently combined withrespiratory acidosis.8'9 The metabolic acidosis de-velops from the accumulation of acid metabolitesduring a period of low perfusion of tissues andobligatory anaerobic glycolysis. Clinical and experi-mental observations indicate that there is a dimin-ished response to intravenous sympathicomimeticagents in patients or experimental animals withacidosis.5'l10'1 This diminished response is mostnoticeable with respect to myocardial function.

Respiratory acidosis frequently occurs with theinduction of anesthesia and in prolonged operations,particularly within the chest.2 This acid-base defectcan be associated with disturbances in cardiovascu-lar function such as acute cardiac arrhythmia.6Maier and coworkers observed a high incidence ofpostoperative hypotension in patients with severerespiratory acidosis (blood pH less than 7.1).6 Car-diac arrhythmia is most likely to occur on the suddenreturn to breathing of room air following a periodwhen the patient has been subjected to high con-centrations of carbon dioxide with its associatedrespiratory acidosis.3'7

Acute Pancreatitis: The great masquerader of theupper abdomen is acute pancreatitis. The suddenonset of circulatory collapse may be the first evi-dence that this disease is present. Several mecha-nisms predispose to circulatory failure in thiscondition. One is the extensive loss of plasma in theretroperitoneal tissues due to the acute inflammatoryprocess. A second is the sequestration of wholeblood in acutely congested blood vessels in the areaof acute inflammation. Still another is the loss ofprotein-rich fluid into the peritoneal cavity as aresult of the acute peritonitis. The net result of thesefactors is a reduction in the plasma volume and adecrease in the effective circulating whole bloodvolume. This disease should always be suspected

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when unexplained circulatory failure follows anyoperation, but particularly following biliary orgastric operation.

Vascular Impairment of the Bowel: One of themost insidious causes of refractory hypotension isintestinal obstruction due to mesenteric vascularocclusion. There may be vague abdominal symptomsearly in the illness and the radiologic observationsmay be equivocal. The first sign that bowel infarc-tion exists is the onset of vascular collapse. Promptdiagnosis and definitive operation are essential forsurvival.

Acute Adrenal Insufficiency: Refractory hypoten-sion in a patient with a history of tuberculosis orthe presence of advanced malignant disease raisesthe possibility of acute adrenal insufficiency due tothe destruction of the gland or replacement by tumortissue. The widespread use of corticosteroid drugsin the management of a variety of chronic medicaldiseases poses an additional problem of recognizingrelative adrenal insufficiency. A history of recentsteroid therapy should alert the examining physicianto the possibility of vascular collapse due to thiscause.

DIAGNOSIS

In dealing with refractory hypotension, criticalevaluation is needed to establish an accurate diag-nosis and to institute specific therapy. Often a de-tailed history and physical examination will elicitadditional information that may explain the circu-latory failure. Table 1 outlines laboratory studiesthat are helpful in determining the cause of un-explained hypotension. Several points should beemphasized in regard to the use of these studies.

Blood: Serial hematocrit or hemoglobin determi-nations frequently demonstrate evidence of loss ofplasma or extracellular fluid. A rising hematocritor hemoglobin value indicates plasma loss, the causeof which must be determined by further clinicalevaluation. Acute hemorrhage is not associated withan immediate drop in the hematocrit or hemoglobinvalue, since transcapillary refilling of the plasmavolume must take place before the reduced red cellmass can be diluted. Serial determinations of hemo-globin and cell volume are essential if this changeis to be demonstrated.Plasma electrolyte determinations should be ob-

tained if change in cerebration, evidence of neuro-muscular irritability or unexplained hypotensiondevelops. In prolonged surgical illnesses in whichoral intake of fluids or food has been impossibleor there has been excessive loss of fluids and elec-trolytes through nasogastric or fistula drainage, itis well to make determinations frequently to insurethe adequacy of replacement therapy.

TABLE 1.--Suggested Diagnostic Studies In UnexplainedHypotensIon

A. BLOOD:Serial hematocrit or hemoglobin determinationsPlasma electrolyte contentCarbon dioxide contentAmylase contentCultures

B. X-RAY OBSERVATIONS:Postero-anterior film of chestPlain film of abdomenLateral decubitus film of abdomen

C. ELECTROCARDIOGRAMD. ADRENAL CORTICAL EVALUATION:

Eosinophil countPlasma corticosteroid concentration"Corticosteroid infusion test"

In clinical situations in which the initial carbondioxide combining power is abnormally high or lowor the patient has acute and unexplained respiratorychanges, determination of the pH and the total car-bon dioxide content of the arterial blood is mosthelpful in establishing an accurate diagnosis of theacid-base disorder which may be present. A pHdetermination is necessary to indicate whether alow carbon dioxide combining power is due tometabolic acidosis or respiratory alkalosis.Serum amylase determination is another helpful

diagnostic test in unexplained hypotension. A risinghematocrit or hemoglobin value following operationon the biliary tract or the stomach is an indicationfor the measurement of amylase activity, particu-larly if there is evidence of circulatory failure.The onset of temperature elevation followed by

vascular collapse is evidence of bloodstream infec-tion and is indication for obtaining multiple bloodcultures. The more cultures drawn, the more likelyis identification of the organism. Then sensitivitystudies can make antibiotic treatment more effective.X-ray Observations: X-ray examination of the

chest and abdomen is frequently helpful in estab-lishing the cause of unexplained hypotension. Un-suspected pneumothorax, pneumonia or bowel ob-struction may be demonstrated. Occasionally it ispossible to see free intraperitoneal air or fluid levelson the lateral decubitus view of the abdomen.

Electrocardiogram: It is advisable to obtain anelectrocardiographic tracing on all patients with un-explained vascular collapse and to interpret it withcare. S-T segment changes and nonspecific T wavechanges can occur as a result of myocardial ischemiafollowing the onset of a hypotensive incident.

Adrenal Cortical Evaluation: Acute adrenal cor-tical insufficiency can be diagnosed by actual meas-urement of the plasma corticosteroid levels* or byan eosinophil count. The presence of a normal num-

The term corticosteroid is used herein to mean 17-OH corticos-teroid.

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ber of circulating eosinophils in a patient with cir-culatory stress is evidence of adrenal insufficiency.If serious question exists that adrenal failure maybe the cause of the vascular collapse, the administra-tion of intravenous hydrocortisone as an "infusiontest" should promptly solve the problem. This testwill be discussed later in this paper.

MANAGEMENT

The aim of treatment in refractory hypotensionis the restoration of adequate perfusion to vital or-gans at the earliest possible time. Blood pressurealone does not always reflect the status of organ per-fusion or capillary circulation. One must considerthe mental status of the patient, vital organ function(such as urinary output) and the general clinicalappearance. The following treatment routine hasbeen found helpful in restoring circulatory homeo-stasis in problem cases.

Correction of Electrolyte Disorders: Any demon-strable electrolyte disorder should be corrected, par-ticularly any evident deficit of the sodium ion. Acutelosses of sodium are frequently associated withextracellular fluid volume reduction in surgical pa-tients. One must be careful to distinguish acutesodium deficit from a low plasma sodium concen-tration of dilutional origin produced by over-ad-ministration of electrolyte-free solution during thepost-traumatic period of antidiuresis.We have observed beneficial results by the ad-

ministration of concentrated sodium solutions topatients with refractory hypotension who had lowplasma sodium concentrations.9 The use of hyper-tonic saline solutions (3 per cent or 5 per centsodium chloride) allows the correction of acutesodium deficiency without the administration of ex-cess water. The coexistence of hyponatremia andmetabolic acidosis makes sodium bicarbonate orlactate the ideal repair solution. One cannot postu-late that all patients in shock will benefit by the useof concentrated sodium salts. The sodium therapymust be matched to the particular deficit observedin each instance.

Correction of Acid-Base Disorders: As previouslymentioned, the two commonest disorders of acid-base balance in patients with refractory hypoten-sion are metabolic acidosis and respiratory aci-dosis.8'9 Sodium bicarbonate or lactate is usefulin correcting any existing metabolic acidosis. Itshould be borne in mind, however, that the admin-istration of base cannot be expected to restore anormal hemodynamic state in the presence of anuncorrected deficit in blood volume. Following ade-quate blood volume restoration, the correction of

an associated metabolic acidosis in a patient withrefractory hypotension might be expected to im-prove cardiovascular function.

The most important aspect of dealing with respir-atory acidosis is preventing it. Adequate ventilationduring long and extensive operations, encouragingcoughing and deep breathing in the postoperativeperiod, and endotracheal suctioning, particularly inthoracic operations, will help to minimize the threatof respiratory acidosis. Respiratory acidosis is usu-ally difficult to treat once it develops, for there isusually some underlying acute or chronic pulmo-nary disease process such as pneumonia or emphy-sema. The judicious use of tracheostomy whereindicated, and of positive pressure assisted respira-tion, offer the best chance of improvement.

Control of Sepsis: In the case of vascular collapseas a concomitant of severe sepsis, vigorous andprompt control of the infection by a combination ofwell-established surgical principles and intensiveantibiotic therapy offer the best chance for survival.Broad spectrum antibiotics should be administeredin high concentration by the intravenous route sinceintramuscular antibiotics may not be absorbed dur-ing the period of acute vascular collapse. Adminis-tration of whole blood or plasma until the venouspressure [monitoring of central venous pressure isdiscussed later in this presentation] begins to showan elevation has been helpful in restoring circula-tory homeostasis in some of these patients. Acritically ill patient with severe sepsis and vas-cular collapse may show a favorable response toovertransfusion.4

Blood Volume Restoration: Whole blood andplasma are the most important therapeutic agents inthe treatment of refractory hypotension. Althoughone must be concerned about overtransfusion andcongestive heart failure, elderly patients in vascularcollapse are as vulnerable to prolonged under-replacement of blood as they are to sudden over-transfusion. Colloid replacement must be accuratelytailored to the apparent volume requirements of thepatient. The object of this therapy should be to re-store not only the blood pressure but the flow ofblood to vital organs.

Corticosteroid Administration: The diagnostictests for establishing adrenal cortical insufficiencyhave been outlined. In clinical situations in whichurgency demands that it must be determined quicklythat adrenal insufficiency is not the cause of vascularcollapse, the "corticosteroid infusion test" can beused. Solu-Cortef in a dosage of 100 to 300 mg. canbe administered intravenously in 500 cc. of normalsaline solution. Signs of circulatory improvementshould promptly become evident if adrenal insuffi-ciency is the cause.

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Figure 1.-Diagram of a simple disposable venous pressure set.* One vertical limb of the plastic Y is taped tothe intravenous standard on which is placed an adhesive tape scale with zero at the estimated level of the right auricleof the heart. The second vertical limb of the plastic Y is connected to a bottle of normal saline solution and serves asa reservoir for filling the "manometer" limb of the apparatus. Following filling the "manometer" with saline solution,the reservoir side is clamped and the column of saline solution is allowed to seek the level of the patient's venouspressure. Such measurements can be made as often as desired and serve as a constant monitor of myocardial functionrelative to blood volume replacement.

Clinical studies by Anderson and coworkers1 in-dicated that in certain situations, particularly blood-stream infection, the administration of pharmaco-logical doses of hydrocortisone may attenuate thecardiovascular effect of the septic process. The dosein this case would approach a gram per day andwould be continued for a short time only, then grad.ually tapered until discontinued. Such intensive ther-apy awaits further clinical and experimental evalua-tion. The use of this potent drug is not withoutserious complications and should be resorted to onlywhen conventional therapy has failed to restore ade-quate circulation.

Vasopressor Therapy: The use of the potent vaso-pressor drugs in the management of circulatory col-lapse has been the source of considerable contro-

"Made by the Fenwal Laboratories, Framingham, Mass.

v.ersy. In elderly patients we have found these drugsuseful to maintain blood pressure until specifictherapeutic measures have restored adequate circu-lation. Patients under general or regional anesthesiawith diffuse circulatory paralysis likewise respondwell to the temporary use of vasopressor drugs.The apparent improvement in blood pressure fol-

lowing the use of these potent drugs should not lullthe surgeon into complacency. The underlying causefor the circulatory collapse must be determined.Every effort should be made to institute specifictherapy and to discontinue the administration ofvasoconstrictor agents at the earliest possiblemoment.

Care should be taken not to produce an acutedilutional hyponatremia by the over-administrationof 5 per cent dextrose in water relative to the con-centration of vasoconstrictor being used. The fluid

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volume administered should be closely observed andthe concentration of vasoconstrictor drug increasedwhen fluid intake exceeds actual body requirements.

GUIDES IN TREATMENT

The objective of the therapeutic program to beused in patients with circulatory collapse is themaintenance of adequate perfusion to vital centersand the restoration of circulatory homeostasis atthe earliest possible time. Several indices are helpfulin the management of these patients. These includeobservation of the state of consciousness, vital signsand hourly urinary output, monitoring the centralvenous pressure and the serial determination of thehematocrit or hemoglobin. An alert patient withadequate urinary output is not in serious dangereven though the blood pressure may have fallen.By contrast an elderly hypertensive patient who isstuporous and oliguric is in immediate danger eventhough the blood pressure may still be within anormotensive range.

In acute circulatory disturbances the productionof urine usually reflects the status of the blood vol-ume. If there is a blood volume deficit, oliguria en-sues. Hence the value of the hourly urinary outputin determining whole blood or plasma volume defi-cits in refractory hypotension. A rising hourly urineoutput concomitant with colloid administration in-dicates favorable progress in restoring the bloodvolume. The urine output should range between 30and 60 cc. per hour.

Central venous pressure is another helpful guidein determining the adequacy of colloid administra-tion in patients with refractory hypotension. A poly-ethylene catheter (the size of a 14 gauge needle) isplaced in a large arm vein and inserted to the axil-lary or subclavian level. The venous pressure is thenmeasured at frequent intervals by observing theheight of a column of saline solution in the verticallimb of a disposable venous pressure set. Zero is atthe estimated level of the right auricle. Figure 1shows such a venous pressure set.* Colloid adminis-tration can be safely continued as long as the venouspressure remains stable. A rising venous pressureindicates overexpansion of blood volume relative tomyocardial function. In such a situation, the rate oftransfusion must be curtailed and the patient digi-talized; or, if the patient's condition has becomestabilized, consideration should be given to vene-section. In our experience, the serial observationof the central venous pressure has been more help-ful in determining the colloid requirement of pa-tients with refractory hypotension than has actualmeasurement of the blood volume, which all too fre-

quently shows the volume to be normal or increased,yet the patient remains in circulatory collapse.

DISCUSSION

There is a growing tendency to consider circula-tory collapse or shock as a primary diagnosis ratherthan to recognize it for what it is-a sign of a seri-ous underlying complication. Too frequently a pa-tient with refractory hypotension is considered tobe in "irreversible shock." It should be pointed outthat no clinical test or criteria are available to de-termine when a patient has become refractory to alltherapy, and "irreversible" therefore has no placein clinical service except possibly in viewing sucha problem case in retrospect.

Circulatory collapse as we see it on the clinicalservice is different from that produced in the labora-tory. This condition frequently occurs in elderlyarteriosclerotic patients with degenerative diseasesinvolving multiple organs. This is in contrast to thehealthy laboratory animal with no degenerative orsignificant arteriosclerotic changes. The presence ofdiffuse arteriosclerosis makes specific treatment im-perative and requires greater vigilance during ther-apy if the patient is to survive.Loma Linda University School of Medicine, 1700 Brooklyn Avenue,

Los Angeles 33 (Smith).

*Available from the Fenwal Laboratories, Framingham, Massa-chusetts.

REFERENCES

1. Anderson, G. V., and Marshall, K.: Septic abortionwith vascular collapse, West. J. Surg. Obstet. and Gyn., inpress.

2. Beecher, H. K.: Acidosis during thoracic surgery, J.Thor.-Surg., 19:50, 1950.

3. Brown, E. B., Jr., and Miller, F.: Ventricular fibrilla-tion following rapid falling alveolar carbon dioxide concen-tration, Am. J. Physiol., 169:56-60, 1952.

4. Ebert, R. V.: Discussion of Septic Shock at the Con-ference on Recent Progress and Present Problems in theField of Shock, Walter Reed Army Hospital, Washington,D. C., Dec. 14.17, 1960.

5. Houle, D. B., Weil, M. H., Brown, E. B. Jr., and Camp-bell, G. S.: Influence of respiratory acidosis on ECG andpressor responses to epinephrine, norepinephrine and meta-raminol, Proc. Soc. Exp. Biol. and Med., 94:561-564, 1957.

6. Maier, H. C., Rich, G. W., and Eichen, S.: Clinicalsignificance of respiratory acidosis during operations, Ann.Surg., 134:653-658, 1951.

7. Miller, F. A., Brown, E. B. Jr., Buckley, J. J., Van-bergen, F. H., and Varco, R. L.: Respiratory acidosis: Itsrelation to cardiac function and other physiologic mecha-nisms, Surg., 32:171-183, 1952.

8. Smith, L. L., Hamlin, J. T. III, Walker, W. F., andMoore, F. D.: Metabolic and endocrinologic changes inacute and chronic hypotension in man, Metabolism, 8:862,1959.

9. Smith, L. L., Ball, M. R., and Moore, F. D:. Clinicaland biochemical observations in refractory hypotension inman. Submitted for publication to Annals of Surgery.

10. Thrower, W. B., Darby, T. D., and Aldinger, E. E.:Acid-base derangements and myocardial contractility, Arch.Surg., 82:56, 1961.

11. Weil, M. H., Houle, D. B., Brown, E. B., Campbell,G. S., and Heath, C.: Influence of acidosis on the effective-ness of vasopressor agents, Circulation, 16:949, 1957.

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