Tissue hypoxia in surgical practice

Tissue

Hypoxia MECHANISMS

in Surgical AND

Practice

MANAGEMENT*

JAMESD. HARDY, M.D., Jackson, Mississippi Department of Surgery and University Hospital, University of Mississippi Medical Center, Jackson. Aided by Army Contract No. DA-pg-oo7-MD-627.

MAJORsegment of the therapeutic activity on most surgica1 services is directed toward the prevention and treatment of hypoxia at the tissue IeveI. Acute hypoxia may require immediate corrective measures if the patient or perhaps an organ is to survive. Chronic hypoxia is aIso a probIem of much concern to the surgeon, for repair of the structura1 defect may require a most deIicate and meticuIous type of surgery. If anoxia deveIops abruptIy and is not soon reIieved, gangrene of

A

MECHANISMSOFHYPOXIA B-

DEFECTIVE

VENTILATION

m a.Venfilat~on

HEART- Inadequate wtput

b Olffusnn c. Perfusion

_w a. lnodequote volume VENOUS

PRESSURE

b. Defective composition c Defective hemoglobin ARTERIAL

SYSTEM

o. Atherosclerosis c. Thrombosis d Loss of tonus CELL 8 COMFWENTS q. Rotesof O~utilizatiw,

MICROCIRCULATION

0 02content b. Pressure c Stasis

FIG. I. The diagram ikstrates numerous factors which may influence the amount of oxygen delivered to the ceII and its component parts. * AnnuaI Honor Lecture American

Journal

of Surgery.

Volume

dehvered

106, September

the tissue invoIved wiI1 often ensue. When hypoxia deveIops sIowIy, as in tissues suppIied by increasingIy atheroscIerotic arteries, gradua1 atrophy of various eIements of the organ wiI1 occur prior to eventua1 gangrene. Hypoxia commonIy results in metabolic acidosis that is secondary to anaerobic metabolism, and this acidosis is deIeterious to ceIIs apart from other effects of hypoxia per se. The factors which may diminish the amount of oxygen deIivered to and utilized by the ceI1 and its parts are often so compIex as to defy comprehensive identification in the emergency. (Fig. I.) And yet, the effective treatment of hypoxia at the tissue IeveI often requires at Ieast a proximate understanding of the physioIogic defects which may be responsibIe for failure of the oxygen suppIy at the periphery. AdmittedIy, the factors which inffuence the efficiency with which the component parts of the ceI1 utilize oxygen to continue their respective biochemica1 processes must await further study. Such investigations may invoIve rates of uptake of IabeIIed atoms such as carbon by the nucleus, the mitochondria and the microsomes of the ceI1. But regardIess of what defects the expIoration of the subceIIuIar frontiers may disclose in the future, much is currentIy known with respect to factors which affect delivery of oxygen to the confines of the ceI1 membrane, and it is to these considerations that attention will be principaIIy directed. In generaI, the course of oxygen wiI1 be traced through the trachea and the Iungs, to the heart, out with the cardiac output, through the arteria1 system, into the microcircuIation, and through the interstitia1 fluid to the ceI1. Defects in each of these conduits wiI1 be noted, and the discussion wiI1 proceed according to the foIlowing 0utIine:

before the Pittsburgh

1963

476

Surgical

Society,

May 28, 1962.

Tissue

Hypoxia

in SurgicaI

Practice

FIG. 2. Huge Iung buIIa or “cyst.” RemovaI of the Iesion, which was attached to the right upper Iobe aImost by a pedicIe (rigbt), markedly increased the Iung voIume on both the ipsiIatera1 and contraIatera1 sides. VentiIation was much improved.

I. Respiration A. Ventilation B. Diffusion C. Perfusion 11. CircuIation A. Heart B. BIood-VoIume and Composition C. VascuIature I. ArteriaI System 2. MicrocircuIation 3. Venous System 4. Lymphatic drainage D. InterstitiaI and IntraceIIuIar FIuids

VENTILATION

The commonest respiratory probIem in cIinica1 practice is probabIy defective ventiIation, and this may occur in many different cIinica1 situations. It may have resuIted from nervous system dysfunction either in the brain or in the spina cord, from trauma with rib fractures and a fIai1 chest, from reduced Iung voIume due to a space-occupying Iesion such as a Iarge Iung cyst (Fig. 2), from obstruction of a main stem bronchus by tumor or inspissated secretions, or from genera1 debiIity of the patient. In most of these instances the ventiIatory defect is one of inadequate tida1 voIume rather than of uneven ventiIation of the individua1 aIveoIi. The composition of the inspired gas rareIy constitutes a probIem unless the patient is under anesthesia, when defective removal of carbon dioxide by the soda-Iime cannister in a cIosed system may permit serious respiratory acidosis to occur due to the rebreathing of carbon dioxide. However, in the absence of the rare circumstance of carbon monoxide poisoning, the quaIitative aspects of the inspired gas occasion IittIe respiratory diffkuIty of significance in the preoperative patient. The mechanica aspects of ventiIation and the work required to maintain an adequate minute voIume are, however, of much sign%cance. For exampIe, the patient with airway

RESPIRATION

It is often instructive to consider puImonary and cardiac activity as a unit, as cardiopuImonary function. For many dimensions of the two do in fact overIap, are interdependent and, thus, in many ways inseparabIe. As an exampIe, the puImonary circuIation derives from the force of the myocardium, whiIe myocardia1 activity is dependent upon an adequate suppIy of oxygen from the Iungs. NevertheIess, there are specific capacities and defects which are pecuIiar to each organ, and it is convenient to consider the respiration and cardiac functions individuaIIy. The three major components of respiration are ventiIation, diffusion and perfusion, and any one of these may be defective in the given patient. 477

Hardy

FIG. 3. Vomiting with puImonary aspiration and hypoxia. (Leff.) Preoperative chest roentgenogram. (Right.) PortabIe chest roentgenogram taken shortIy folIowing operation. As genera1 anesthesia was being initiated the patient vomited a large voIume of Ruid, and massive puImonary aspiration of this material occurred. In the current absence of an efficient method for extracorporea1 support of respiration in the patient who has uItimateIy reversibIe respiratory insuficiency, the man eventualIy died of proIonged hypoxia (see text). Aspiration pneumonitis is common.

as the patient emerges from anesthesia, if a cuffed endotrachea1 tube has protected the patient during the course of the operation. In addition to bronchoscopy, nasotrachea1 aspiration, and postura1 drainage prior to operation, the anesthesioIogist wiI1 wish to exercise great care to remove excessive amounts of secretions from the airways during operation. In any patient who has had intestina1 obstruction preoperativeIy, the possibiIity of Iiquid in the stomach should be considered and a nasogastric tube introduced and the stomach decompressed, even though the patient may have taken nothing by mouth for a great many hours or even days. In Figure 3 are shown a preoperative chest roentgenogram and a portabIe chest roentgenogram taken immediateIy postoperativeIy in a patient who was admitted to a hospita1 with suspected smaI1 bowe1 obstruction. Since the patient had not been vomiting, a nasogastric tube was not passed preoperativeIy. UnfortunateIy, as anesthesia was being induced the patient vomited and aspirated materia1 into the Iungs. The result was a massive contamination of the Iungs with materia1 from the stomach, and, after severa days of severe hypoxia, the patient died. During this period a11 avaiIabIe measures were empIoyed to minimize the hypoxia to vita1

obstruction or severe asthmatic bronchia stenosis may expend so much energy in the ventiIatory effort that the additional oxygen uptake is consumed by the excessive muscular exertion. Thus, miId sedation wiI1 often improve the over-all eficiency of respiration and resuIt in the deIivery of more oxygen to the tissues whiIe Iowering tissue oxygen requirements. Moreover, excessive respiratory effort may Iead eventuaIIy to exhaustion, when ventiIatory inadequacy may resuIt in tissue hypoxia and death. An important cause of inadequate puImonary ventiIation is the presence of foreign materia1 or mucus in the bronchial passages. This may represent material from a Iung abscess, inspissated secretions or gastric contents. Thus, bronchia obstruction may occur during anesthesia in patients who have bronchiectasis, Iung abscess, hemoptysis, or a stomach distended with ffuid from any cause. The air passages must be cIeared of such materiaIs at al1 times, for not onIy does this improve puImonary ventiIation, it aIso faciIitates the induction of anesthesia. One of the more common causes of preventabIe deaths associated with major surgery is the hypoxia which results from aspiration of materia1 into the Iungs during the course of induction of anesthesia or 478

Tissue

Hypoxia

in Surgical

centers and other tissues. A tracheostomy was promptIy performed and intermittent positive pressure breathing assistance was instituted. The stomach was kept decompressed at a11 times to prevent further risk of aspiration and to diminish the effect on puImonary ventilation which a distended stomach might impose. Detergents, mucoIytic agents, humidification, bronchodiIators, hydrocortisone and aminophyIIine were empIoyed to reduce in so far as possible the inffammatory effects of the acidpepsin factor of the gastric juice upon the lungs. Hypothermia was employed to prevent fever and to diminish the tota oxygen requirements of the body. During the postoperative period, the patient received norepinephrine without which the bIood pressure couId not be obtained. Support During Acute Respiratory Insujiciency. The case described above represented an exampIe of the current need for reIativeIy long-term support of the patient with a reversibIe but temporariIy incapacitating puImonary insuffIciency. Had it been possibIe to support the patient during the postoperative period whiIe the effects of the massive aspiration pneumonitis were being dissipated, he wouId almost certainIy have Jived. The bIood pressure was supported and a11 possible ventiIatory assistance was empIoyed, but the major defect Iay in the smaIIer bronchioIes and in the aIveoIi, which were not we11 ventiIated. At present it is not feasible to empIoy cardiopuImonary bypass for the tempocary management of respiratory faiIure. The reason for this is that the passing of the bIood through the pumpoxygenator is sufhciently traumatic that excessive hemoIysis and pIateIet destruction occur after a few hours. The possibiIity of the intravenous infusion of oxygen, either as a gas or as a soIution of hydrogen peroxide, has intrigued various investigators over the years; however, at the present time too IittIe oxygen can be given in a gaseous form, and the intravenous infusion of hydrogen peroxide, perhaps with added cataIase, resuIts in the formation of methemogIobin [I]. The administration of oxygen at three atmospheres of pressure, using the Boerema [2] tank, might be heIpfu1 under some circumstances, but adequate experience is as yet Iacking. NevertheIess, this method of markedIy increasing oxygen carried in the may pIasma, which at three atmospheres

Practice

almost equa1 that carried by hemogIobin, being investigated in many clinica centers.

is

DIFFUSION

Diffusion defects are more diffIcuIt to investigate than are pure ventilatory defects, but they are no Iess important. ExampIes of diffusion pathoIogy may be cited: Aside from interstitia1 edema or aIveoIar membrane changes which render passage of oxygen and carbon dioxide to and from the puImonary capiIIaries less faciIe, there must exist an adequate aIveoIar membrane surface to permit sufficient diffusion. For exampIe, even in the absence of pulmonary resection, the patient with severe emphysema or “vanishing Iung” may have so few remaining aIveoIi, with supporting vascuIar eIements, that norma arterioIization of the bIood cannot occur in the Iungs regardIess of the minute voIume of ventiIation. Although not entireIy a diffusion probIem, there is evidence that the aIveoIar membranes may suffer damage during the course of cardiopulmonary bypass, and foIlowing open heart surgery many patients demonstrate various degrees of the so-caIIed congestive ateIectasis. (Fig. 4.) Often one of the most usefu1 adjuncts

FIG. 4. Positive

pressure ventiIatory assistance. In a nine year oId girI pulmonary congestion deveIoped foIIowing cIosure of a Iarge atria1 septa1 defect on cardiopulmonary bypass. The use of tracheostomy and ventiIatory assistance was Iifesaving in this instance, as it is in many other forms of reversibIe respiratory insuflkiency.

479

Hardy PERFUSION

FIG. 5. Compression of the great veins and branches of the puImonary artery by idiopathic mediastinal fibrosis. Hypoxia with dyspnea and cyanosis was present in this patient.

in the management of DuImonarv diffrcuhies in the postoperative period folIowing cardiopulmonary bypass is to perform a tracheostomy and empIoy intermittent positive pressure breathing, using one of the various how sensitive or pressure sensitive respirators that are commerciaIIy avaiIabIe. UtiIized with aid of detergent aerosoIs and mucoIytic agents, these instruments permit the patient a greater voIume of ventiIation than the oatient can or wiI1 provide for himseIf. Even &Idren wiI1 request that the ventiIatory assistance be reinstituted when they begin to become hypoxic and excited due to this often terrifving exoerience. Needless to sav, the use of-a puffed tracheostomv tube and one of the various respirators must be supervised continuousIy by a person comDIeteIv familiar with the hazards involved. The cuff of the tracheostomy tube may become deflated, the tracheostomy tube may become pIugged, or the respirator may become detached from the tracheostomy tube. The function of the respirator itseIf may be defective, in which case the fact that the machine is connected to the cuffed tracheostomv tube resuIts in an even greater hazard of asphyxia than if the patient had been Ieft without such a device. I

Y

480

The third eIement of puImonary function, perfusion of the Iungs by means of the puImonary artery and the corresponding veins, is occasionally defective. This inadequate perfusion of the Iungs is most IikeIy to be encountered in the presence of cardiac defects associated with puImonic stenosis, or with occIusion of various branches of the puImonary artery by emboIi, and with compression of branches of the puImonary artery as in idiopathic mediastinal fibrosis. (Fig. 4.) The clinica roIe of possibIe spasm of the puImonary arteries, suggested where emboIic occIusion of a reIatively smaI1 branch has been associated with a fatal outcome, remains in doubt. PuImonic stenosis can be surgicaIIy corrected, and successfu1 pulmonary arteria1 emboIectomy using cardiopuImonary bypass has been reported [J]. The externa1 compression of branches of the puImonary artery by idiopathic mediastina1 fibrosis is not readiIy amenabIe to surgica1 correction, due to the tremendousIy dense and adherent nature of the coIIagenous connective tissue which forms a thick sheath around the branches of the puImonary artery. NevertheIess, this condition has been reported to improve spontaneousIy, at times aided by steroid if interference with the therapy. Otherwise, puImonary circuIation is severe and the condition cannot be relieved at operation, the patient may not survive the postoperative period. MANAGEMENT PROPHYLACTIC

OF RESPIRATORY AND

INSUFFICIENCY:

THERAPEUTIC

MEASURES

The management of respiratory difficulty begins in the preoperative period. The routine chest roentgenogram wiI1 excIude major spaceoccupying Iesions which could diminish the efficiency of respiration during and foIIowing anesthesia. Lung function studies are often indicated, especiaIIy prior to thoracotomy which may or may not invoIve puImonary resection. Thus, preoperativeIy any pIeura1 effusion, pneumothorax, pneumonitis or ateIectasis can be treated appropriately. Excessive bronchia secretions due to chronic bronchitis, bronchiectasis or lung abscess can be markedIy reduced in voIume by postura1 drainage, cessation of smoking, antibiotic therapy, and the use of aeroso1 detergents, mucoIytic agents and upon occasion hydrocortisone, especiaIIy

Tissue

Hypoxia

in asthmatics.

Frequent intratrachea1 aspiration and even bronchoscopy may be utilized, but these are not often required in the preoperative period. As noted above, the patient with aIimentary obstruction shouId be treated with nasogastric suction to diminish the hazard of puImonary aspiration during anesthesia. During operation the anesthesioIogist wiII be aIert to maintain a patent airway, cIear of secretions. Adequate pulmonary ventiIation wit1 incIude the effective infIation of a11 parts of the Iung, which wiII ordinariIy require assisted ventiIation, and for operations that are to Iast more than a brief period the use of the endotracheaI tube is essentiaI to safety. Effective ventiIation with the proper gas mixture during operation wiI1 achieve efficient elimination of carbon dioxide to prevent the deveIopment of respiratory acidosis, and it wiII prevent the development of hypoxia. Postoperatively, the probIem of respiratory insufficiency may be present in an acute form. This may be due to the prolonged effects of the anesthetic agent or of the muscIe reIaxant drug, or to hypotension which partiaIIy obtunds the sensorium and results in an inadequate minute voIume of ventiIation. A degree of puImonary edema, minor pneumonitis, tenacious tracheobronchia1 secretions with patchy atelectasis, and a painfu1 postoperative wound may al1 reduce respiratory efficiency. This may be reffected in hypoxia and perhaps a mixed respiratory and metaboIic acidosis. These conditions are treated by various measures that have been outIined previousIy. In addition, the cough reffex may be stimuIated and inspissated secretions liquefied by means of a mucoIytic agent injected through a smaI1 inIying pIastic catheter introduced percutaneousIy through the cricothyroid membrane into the trachea [4,3]. Again, a most important adjunct for improvement of postoperative respiration in criticaIIy iI patients has been the use of assisted positive pressure ventilation. CIRCULATION

The respiratory apparatus deIivers oxygenated bIood to the left atrium, and the systemic circulation delivers it to the peripheral capiIIary Ievel and through the interstitial ffuid to the ceI1. The eIements of the circulation which maintain an adequate perfusion pressure, or systemic arteria1 bIood pressure, wiI1 now be

in Surgicai

Practice

considered separateIy. These factors are the heart, blood voIume and periphera1 resistance. HEART

The function of the heart is to pump the bIood deIivered to it. Lesions affecting the heart which seriousIy reduce cardiac output through the aorta include intracardiac shunts, vaIvuIar defects, myocardia1 disease, conduction mechanism disorders, and compression as by pericardial tamponade or constrictive pericarditis. There is evidence that hypoxia may seriousIy damage the conduction mechanism in the heart, perhaps Ieading to sudden death in some instances [6]. Although it is wideIy appreciated that heart faiIure may resuIt in cyanosis and other manifestations of tissue hypoxia, it is perhaps Iess we11 known that acute myocardia1 infarction with resuIting shock may produce symmetrical gangrene of the Iower extremities (71, or that severe aortic regurgitation without shock may resuIt in gangrene of the intestine suppIied by the superior mesenteric artery [8]. Therapeutic Measures. The probIems associated with inadequate cardiac output Ieading to hypoxia are too diffuse to be considered here. Suffice it to say that digitalization and the use of diuretics are frequentIy heIpfu1 in rendering patients with overt or incipient heart faiIure better operative risks. BLOOD

The maintenance of an adequate volume of bIood of the proper composition, with respect to both pIasma and red ceI1 components, is extremely important in preventing both acute and chronic hypoxia. BLOOD VOLUME

PhysioIogic equilibrium requires that the bIood volume be adequate but not excessive. Moreover, the composition of the bIood shouId remain within restricted Iimits, with an appropriate voIume of norma red blood ce1l.s reIative to a pIasma which contains an adequate amount of pIasma protein of norma composition. A reduced bIood voIume may be the result of either a deficit in pIasma or in red blood cells, or both. Similarly, when an excessive blood voIume exists it may represent an excess of either pIasma or red bIood ceIIs or both. The voIume of red bIood celIs is normalIy regulated by subtIe physioIogic feedback mecha-

Hardy I

P

1

.

1

6

transfusions at appropriate rates unti1 the hemogIobin and hematocrit IeveIs have approached the norma vaIues. The excess pIasma protein enters the genera1 metabolic poo1 and the water is excreted, Ieaving Iargely the trans fused red bIood ce1Is in the circulation [II] to transport oxygen to the tissues. The hematocrit IeveI may be either increased, decreased or unchanged in the presence of a reduced or increased tota bIood voIume. BIood voIume measurements are most commonIy made using the Iarge vein hematocrit IeveI and the bIue dye for measurement of pIasma voIume, though there is an increasing cIinica1 use of isotopic measurements with IabeIIed red bIood ceIIs and radioactive serum aIbumin. WiIIiams and Fine [rz] have recently introduced the voIemeter for the rapid and repeated measurement of bIood voIume. Many patients who exhibit diminished hemoglobin and hematocrit IeveIs preoperativeIy may actuaIIy have a red blood ceI1 mass which is appropriate to the greatIy diminished Iean body mass, perhaps due to weight Ioss secondary to a maIignancy. NevertheIess, patients who are anemic preoperativeIy frequentIy withstand anesthesia and operation more satisfactorily if they are given transfusions prior to the operative procedure. Furthermore, it has been shown that in many patients the Iowered hemogIobin and hematocrit IeveIs do in fact reflect a seriousIy diminished red blood ceI1 mass and total bIood volume. The repIacement of acute bIood Ioss is a matter of greater urgency than is the repIacement of chronic blood 10s~. Where massive hemorrhage has recentIy occurred or is continuing, the tota bIood voIume is often inadequate to permit the maintenance of an adequate systemic arteria1 blood pressure, and shock deveIops. If the patient is given transfusions promptIy with suficient quantities of bIood, the hypotension can be overcome, provided the hemorrhage has been stopped, and irreversibIe shock wiI1 not occur. In fact, few therapeutic efforts are more gratifying than the immediate repIacement of massive brood Ioss with massive transfusion. (Fig. 6.) In contrast to the repIacement of chronic bIood volume deficits, in the presence of hypotension due to acute bIood Ioss the hemogIobin and hematocrit IeveIs are of reIativeIy IittIe assistance as guides to blood repIacement. Here the systemic arteria1 bIood pressure, the puIse

7

FIG. 6. Massive hemorrhage from Iarge peptic ulcer in a maIe patient, R. R., forty-two years of age, No. 62966. Massive bIood Ioss promptly repIaced. It may be seen that the rapid transfusion of 3 L. of bIood to replace previous and continuing Ioss, plus concurrent operation to stop the hemorrhage, promptIy restored the bIood pressure and puIse rate to normal.

nisms which are IargeIy unknown but which may be reIated to the production of erythropoietin [g], in the kidney and elsewhere. The pIasma voIume is reIated to the total extraceIIuIar fIuid voIume, the latter being composed of the pIasma and the interstitia1 fluid. Thus, a reduced circuIating pIasma voIume is often a reflection of a reduced extracelIuIar fIuid voIume. The diminished extraceIIuIar voIume may reflect, in turn, a reduced intraceIIuIar fluid voIume. In generaI, the extraceIIuIar voIume represents about one-third and the intraceIIuIar fluid voIume two-thirds of the tota body water, accounting for approximateIy one-fifth and two-fifths of the body weight, respectiveIy [IO]. A reduction in extraceIIuIar and thus pIasma voIume is commonIy associated with “hemoconcentration,” manifested by an eIevated bIood hematocrit IeveI if the red bIood cells were present in norma voIume prior to the dehydration. A patient may exhibit either whoIe bIood loss or pIasma and interstitia1 fluid 10s~. Moreover, when a fluid deficit exists it may represent aImost pure water Ioss or pure saIt Ioss or, more commonly, a mixed deficit with both water and eIectroIytes needed in replacement. Whole Blood Loss. The repIacement of whoIe bIood Ioss is so commonpIace that only a few points need be noted here. In the instance of chronic bIood Ioss, reffected in anemia, the most practicabIe and readiIy avaiIabIe guides to replacement therapy are the hemogIobin and hematocrit IeveIs. The patient is given 482

Tissue

Hypoxia

in SurgicaI

rate, the rate of urine secretion and the genera1 cIinica1 evidence of improved circuIatory stabiIity are empIoyed. Thus, in an acute emergency the repeated measurement of the bIood pressure is the best guide to proximate adequacy of bIood repIacement. To avoid overtransfusion, the venous pressure may be continuousIy monitored and transfusion sIowed if the venous pressure begins to rise. However, once the bIood pressure has risen above the shock IeveI, further transfusion shouId be continued with caution regardIess of whether or not venous pressure measurements are employed. Red Blood Cell Deficits. Red bIood ceI1 deficit in the absence of a correspondingIy severe pIasma voIume deficit most commonIy deveIops because of sIow but continuing hemorrhage which graduaIIy produces anemia; it aIso may deveIop in chronicaIIy starved subjects. Red bIood ceI1 deficits are frequentIy encountered in patients with maIignant tumors of the Iarge bowe1, for exampIe. In such persons the pIasma voIume may prove to be within norma Iimits or but sIightIy decreased. Red bIood ceI1 repracement in these subjects may be effected with whole bIood, since the pIasma proteins wiI1 in considerabIe measure enter the metaboIic pool and the water wiI1 be excreted (“pIasma dispersa1”). However, if the patient is in borderIine cardiac decompensation, the required red blood ceI1 replacement may more safeIy be given in the form of packed red bIood ceIIs. Using dogs with induced heart faiIure, it has been demonstrated experimentaIIy that Iess rise in right atria1 pressure foIIows the infusion of a given mass of red brood ceIIs as packed ceIIs than foIIows the infusion of the same number of red blood ceIIs in the form of whoIe bIood [II]. The patient who is anemic may exhibit various signs and symptoms due to reIative hypoxia. These incIude dyspnea on exertion, tachycardia and high output heart faiIure, fainting speIIs due to cerebra1 hypoxia, and perhaps Ieg uIcers. It has been we11 established that severe hypovoIemia, even without overt shock, may occasionaIIy resuIt in irreversibIe ischemia of an aIready precariousIy perfused extremity. Red Blood Cell Excess. The flow changes imposed by an increase in the hematocrit IeveI wiI1 be considered somewhat further at a Iater point, but it may be noted here that in some

Practice

respects a marked excess of red bIood ceIIs can produce tissue hypoxia as sureIy as can a deficit, if in a different way. Severe poIycythemia resuIts in markedIy increased viscosity and brood sIudging, and arteria1 thrombosis with patchy gangrene is not rare in a patient with poIycythemia Vera. Plasma Volume Deficits. ScarceIy second in importance to whoIe bIood voIume and red blood ceI1 deficits are plasma voIume deficits. Loss of extraceIIuIar fIuid produces oIigemia and hemoconcentration due to water and saIt 10s~. These Iosses may be due to “third space” Iosses within the body or to external Iosses through vomiting, diarrhea, or alimentary or biIiary fistuIae. Large amounts of pIasma protein may Ieave the circuIation in the form of exudates. The major “third space” Iosses, or sequestration of fluid within the body, incIude massive ascites and Iosses beneath burn wounds or around major fractures. Peritonitis, perhaps due to perforated peptic uIcer or pancreatitis or stranguIation obstruction, may resuIt in reIativeIy huge Auid Iosses into the peritonea1 cavity, the mesentery, the bowe1 Lumen and the retroperitonea1 space. (Fig. 7.) The Iosses in any of these cIinica1 circumstances can be suffIcientIy severe to produce oIigemic shock and death. Thus, a relatively common cause of tissue hypoxia on cIinica1 services is the hypovoIemia which resuIts from excessive water and saIt 10s~. Low sodium shock represents a specia1 circumstance in which the pIasma (and thus extraceIIuIar) eIectroIyte concentration has been Iowered relative to the extraceIIuIar fluid that is present. Quite aside from volumetric considerations, it has been shown in “pure” saIt Ioss experiments that the administration of the sodium ion constitutes virtuaIIy specific therapy for shock associated with a low extraceIIuIar concentration of this ion [1?,14]. This fact has aIso been borne out cIinicaIIy in a number of patients treated by us. For exampIe, a man who was forming massive ascites foIIowing portacava1 shunt went abruptIy into shock, and his bIood pressure was not improved by 1,700 cc. of rapidIy infused bIood and dextran solutions. But when at this point 300 m1. of 3 per cent sodium chIoride solution were rapidly infused, there was a dramatic return of the sensorium and the bIood pressure IeveI to normaI. A bIood sampIe drawn just prior to 483

Hardy

FIG. 7. FIuid losses in smaI1 bowe1 obstruction. SaIt and water Ioss producing extraceIIuIar ffuid and pIasma deficits. Hypotension and inadequate perfusion of tissues is frequentIy caused by fluid losses secondary to intestina1 obstruction, peritonitis or externa1 aIimentary fistuIas.

infusion of the hypertonic sodium chIoride soIution subsequentIy reveaIed a pIasma sodium IeveI of I 18 mEq. per L. REPLACEMENT

OF WATER

AND

SALT

tion may be indicated at the beginning of therapy. ConverseIy, a markedIy eIevated pIasma eIectroIyte concentration with increased pIasma osmoIaIity indicates the need for a noneIectroIyte containing soIution in the initia1 therapy. In generaI, however, an isotonic eIectroIyte soIution, frequentIy sodium chIoride soIution but often a more baIanced eIectroIyte soIution such as Ringer’s Iactate, is administered, with the kidneys excreting the water or eIectroIyte that is not needed and retaining what is required. The point is, the heaIthy kidney is an extremeIy eff%ient assistant to the surgeon in the management of fluid and eIectroIyte therapy. The ffuids are administered unti1 the cIinica1 evidence of dehydration has receded. The blood pressure shouId rise, the tachycardia shouId subside and the urinary output shouId increase. If previousIy elevated, the hematocrit IeveI shouId decIine and the pIasma eIectroIyte IeveIs shouId be brought to within a reIativeIy norma range over the course of severa days.

DEFICITS

In brief, it may be stated that water and saIt deficits are usuaIIy mixed deficits, and thus an eIectroIyte-containing soIution is commonIy required in reparative therapy. The voIume of ffuid that needs to be repIaced in the dehydrated patient wiI1 depend IargeIy upon the clinica evidence of dehydration, that is, the degree of dehydration which appears to be present. As a gross ruIe of thumb, miId dehydration may require the repIacement of 6 per cent of body weight as fluid, moderate dehydration 8 per cent and, occasionaIIy, severe dehydration IO per cent. In the more advanced states of dehydration, onIy one-half the estimated voIume requirement shouId be given initiaIIy and the cIinica1 status of the patient re-evaIuated before more fluid is administered. Patients of simiIar weight, genera1 body habitus and apparent degree of dehydration may vary markedIy with respect to the improvement derived from a given voIume of fluid. The composition of the ffuid that is to be given the patient depends to considerabIe extent upon the pIasma eIectroIyte values that are obtained. If the pIasma eIectroIytes are found to be markedIy reduced in concentration, then occasionaIIy hypertonic sodium chIoride soIu-

BLOOD

COMPOSITION

Red Blood Cells and Hemoglobin. The capacity of both a red bIood ceI1 deficit and a red bIood ceI1 excess to produce hypoxia of periphera1 tissues has been noted. It shouId be pointed out that abnormaIities of the red bIood ceIIs themseIves, as in sickIing and [32] other states of abnorma1 hemogIobin, may resuIt in a defective oxygen suppIy to the tissues. 484

Tissue

Hypoxia

in SurgicaI

Plasma Protein Abnormalities. Tissue hypoxia may aIso be produced by the presence of cryogIobuIin [IT] and by cryofibrinogen [I 61. These abnorma1 proteins may precipitate when the patient is exposed to coId, and intravascuIar occIusion may result. Patients with arterial occIusive disease of the extremities who exhibit cold sensitivity shouId aIso be investigated for cryoproteinemia [ 171. VASCULATURE

Many of the most important recent advances in the management of tissue hypoxia have come about through the diagnosis and correction of hypoxia due to vascuIar inadequacy. Arterial System. Even though respiration, cardiac activity and bIood volume may a11 be optimaI, tissue hypoxia may stiI1 resuIt from diseases of the conduits which are to transport the oxygenated bIood to the periphera1 tissue IeveI. The Tonus of Peripheral Arteries: Peripheral Resistance. It was pointed out previousIy that an adequate perfusion bIood pressure depended upon adequate heart action, adequate bIood voIume, and adequate periphera1 resistance. The term “periphera1 vascuIar coIlapse” has in the past covered many conditions, some of which shouId perhaps be removed from this category. For exampIe, the peripherovascuIar collapse of adrenocortica1 insuffIciency may we11 be due in part to myocardia1 faiIure [18]. NevertheIess, in certain circumstances, such as in endotoxin shock or foIIowing resection of a pheochromocytoma, the hypotension does in fact appear to be due to defective periphera1 arterial or arterioIar tone_regardIess of any element of hypovoIemia or of possibIe adrenocortica1 insuffIciency in a rare case. This hypotension can resuIt in an inadequate perfusion of vita1 centers such as the brain. In endotoxin shock, however, the strength of myocardia1 contractions appears to be Iittle affected by a direct action of the endotoxin, though inadequate coronary perfusion due to hypotension resuIting from a Iowered periphera1 resistance wiI1 of course eventuaIIy affect myocardia1 activity. As further evidence of the fact that norepinephrine is the norma hormona1 mediator of neurovascuIar tone, it has been demonstrated that patients with postura1 hypotension have a defective eIaboration of norepinephrine (pre485

Practice

sumabIy at the end of postgangIionic sympathetic nerve fibers) when they assume the upright position [19-211. In contrast to conditions in which inadequate periphera1 vascuIar tone is present, excessive arteria1 spasm can produce tissue hypoxia by preventing adequate tissue perfusion. This is to be seen in Raynaud’s phenomenon and Raynaud’s disease, the severe vasospasm of oligemic shock, especiaIIy in parts of the body poorIy perfused because of atheroscIerosis, in the presence of norepinephrine therapy, in the presence of functioning pheochromocytoma metastases [22], and in endotoxin shock due to a perforated viscus [23]. Excessive arteriolar spasm can resuIt in such severe tissue hypoxia that at times gangrene resuIts. Therapy of Peripheral Vascular Collapse. If the possibiIity of oIigemia, defective puImonary ventiIation and cardiac function, and adrenocorticar insuffIciency have been excluded insofar as possibIe, it is usuaIIy reasonabIe to assume that the poorIy defined condition designated as peripheral circuIatory coIIapse or Ioss of periphera1 resistance has deveIoped. And in the Iight of present knowIedge, it is frequentIy justifiabIe to empIoy a vasopressor agent in the management of such patients. In Figure 8 are shown data in a patient who was admitted in endotoxin shock secondary to a gram negative organism producing a urinary tract infection. At the time of admission he was semicomatose and the bIood pressure was approximateIy 70/40 mm. Hg. Neo-Synephrine@ and hydrocortisone therapy were not effective in restoring fuI1 consciousness or in producing a bIood pressure that was within norma Iimits. However, the use of norepinephrine resuIted in an eIevation of the bIood pressure and a prompt return of consciousness. It has frequentIy been demonstrated that if the bIood pressure falls beIow the critica perfusion IeveI, cerebra1 hypoxia wiI1 deveIop and coma may resuIt. However, these factors may be aboIished by the use of a vasopressor agent artificiaIIy to raise the bIood pressure. There can be no question that the use of a powerfu1 vasopressor drug in certain cases can be Iifesaving when a11 other measures have failed. In the absence of urinary output, the drug shouId be administered in as smaI1 a voIume of ffuid as feasibIe, since even if an adequate blood pressure Ievel is eventuaIIy achieved and the vasopressor agent discontinued, severe oIiguria may persist

Hardy

160

8

s

so60.

4Oi 20

1

oc<

A.M~3-24-62-PM-l--AM.-33-25-62-PM-l I

8

12

Illclllcclllrl,L~l,~

5

6

7

9

9 IO II

12 2 4

6

8 IO 12 2 4 6

9 IO 12

FIG. 8. Endotoxin shock, bIood pressure IeveI versus sensorium. Relation of flow-pressure factors to organ function. The diagram iIIustrates the cIinica1 course of a patient admitted in endotoxin shock due to urinary tract infection. An eIderIy man, he became semicomatose whenever the bIood pressure was aIIowed to faI1 beIow IOO mm. Hg systoIic. When Iess efficient vasocontrictor agents, as we11 as hydrocortisone, f&d to restore an adequate blood pressure IeveI, norepinephrine was empIoyed with eventua1 recovery of the patient. For optima1 function, the various organs require a bIood pressure IeveI which wiI1 ensure adequate perfusion, and the brain, heart and kidneys are especiaIIy iIIustrative of this need when atheroscIerosis exists.

for many days. NeedIess to say, every effort should be made to excIude hypovoIemia before a vasopressor agent is resorted to in an effort to elevate the bIood pressure. Arterial Occlusive Disease. The avaiIability of effective surgica1 procedures for the correction of arteria1 occIusive disease has resuIted in a vast surge of investigative and therapeutic activity. The bIood supply to any organ may be diminished by atheroscIerotic deposits, and much has been Iearned regarding symptoms, signs and pressure-ffow reIationships to organs such as the brain, kidney and Iower extremity. In some instances even artificiaIIy maintained hypertension is beneficia1, such as in reducing the risk of cerebra1 ischemia and hypoxia during uniIatera1 occIusion of the interna carotid artery whiIe performing carotid endarterectomy. These patients may aIso be further protected by the use of hypothermia during a period of occIusion of the vesse1. The subject who was previousIy markedIy hypotensive, but whose renal arteria1 surgery has resuIted in normotension, may exhibit a reduced urinary output for severa days whiIe the blood pressure 486

remains at norma IeveIs, foIIowing which the urinary voIume may increase but at the expense of a return of a certain degree of apparentIy obligatory hypertension. The classic advances in the management of cerebra1 hypoxia by carotid endarterectomy, of ischemia of an upper extremity reIieved by subcIavian endarterectomy or bypass, the reIief of intestina1 angina by endarterectomy or bypass of an occIuded segment of the superior mesenteric artery, the treatment of renaI hypertension by renaI arteria1 endarterectomy, and the management of ischemia of the Iower extremities by endarterectomy, bypass or combinations thereof-these operative procedures have served to reIieve states of chronic tissue hypoxia in vast numbers of patients. Blood Rheology [24-261. Tissue hypoxia due to vascuIar disease is affected to a significant extent by rheoIogic factors, the properties having to do with flow of a liquid. And the ffow of bIood through periphera1 arteries is affected by many factors. Among these are the presence or absence of occIusion of various degrees in arteries of various sizes, the flow velocity, and the viscosity of the bIood in vessels of different sizes and at points of obstruction. For exampIe, the higher the hematocrit, the greater the viscosity of the bIood, and thrombosis is Iikely to occur due to diminished veIocity of flow in patients with markedly eIevated hematocrit IeveIs. (Fig. 9.) Burch and DePasquaIe [24,27] have emphasized that viscosity of whole blood is dependent partIy upon the rate of shear. At high veIocities of flow and high rates of shear the viscosity curve tends to flatten or become horizonta1. However, the IineaI veIocity of flow wouId be expected to decrease proxima1 to an area of narrowing in a diseased artery. In segments with Iow rates of bIood flow, the bIood viscosity would increase. Thus, for exampIe, in a patient with coronary atheroscIerosis, the viscosity of bIood with an hematocrit vaIue of 50 voIume per cent may be reIativeIy Iower in the aorta than just proxima1 to a narrowed segment of a coronary artery. Burch and DePasquaIe consider that the significantIy higher incidence of myocardia1 infarction in patients with erythrocytosis may be partIy expIained in this manner. Anemia, on the other hand, wouId be expected to provide some margin of safety, since at a given rate of shear the bIood viscosity is directIy reIated to the hematocrit.

Tissue

Hypoxia

in SurgicaI

Psychic and other stress may be foIIowed by a marked and sudden increase in the hematocrit that psychic IeveI [24]. It has been postuIated stress is associated with changes in bIood fIow, an increase in erythropoietin production and, in turn, an increase in erythrocyte concentration. The amount of cardiac work necessary to maintain bIood flow through pathoIogicaIIy narrowed vesseIs wouId of course be influenced by the viscosity of the bIood. Increased brood viscosity which may be present in stress states, particuIarIy when associated with a lowered bIood pressure IeveI, couId predispose to thrombosis in diseased arteries, especiaIIy in the vicinity of narrowed segments. A flow mechanism of some interest is the fact that foot puIses may be present in a given patient prior to exercise, may disappear during exercise aIong with the deveIopment of evidence of severe foot ischemia, onIy to return foIIowing severa moments of rest. One hypothesis to expIain this repeatedIy observed cIinica1 phenomenon might be that the vasodiIatation in the muscIes of the Ieg resuIts in a shunting of blood away from the main channe1 through the femora1 artery to the dorsalis pedis and posterior tibia1 arteries. In a patient whom we treated [28], there was stenosis of the Ieft common iIiac artery with these Aow phenomena present in the Ieft Ieg and foot. It is not wideIy appreciated that the cross-sectiona area of an artery must be reduced by approximateIy 50 per cent before a significant pressure gradient across the point of obstruction is produced.

Practice

FIG. g. MultipIe areas of necrosis in patient with polycythemia vera. The man had experienced multiple episodes of minor arteria1 thrombosis. Note punctate brownish Iesion on plantar surface of right great toe. Erythrocytosis of significant degree markedIy increases the bIood viscosity, with resultant increased tendency to thrombosis in smaII or abnormalIy narrowed Iarger arteries.

inject heparin, prior to storage of the organ, if success with subsequent transpIantation of the organ is to be achieved [jo]. Acidosis may be aImost as deIeterious to tissue, in the absence of effective circulation, as is the hypoxia itserf. Hypoxia wiI1 quickIy resuIt in anaerobic metaboIism with the production of Iactic acid and the deveIopment of metaboIic acidosis. VENOUS

SYSTEM

MICROCIRCULATION

It has Iong been appreciated that massive and abrupt venous obstruction can produce hypoxia of the part, Ieading even to gangrene. (Fig. IO.) In fact, massive and sudden inferior vena cava1 occIusion may not onIy produce tissue hypoxia of the Ieg through back pressure, stasis and reduced arteria1 flow; it may aIso contribute a degree of arteria1 hypotension through the sequestration of a Iarge voIume of extraceIIuIar fluid in the Iegs. WhiIe some red bIood ceIIs wiI1 be trapped, a reIativeIy greater voIume of pIasma is often trapped, and this may be reffected in an eIevation of the hematocrit IeveI. NormaIIy a11 ceIIs are in a reIativeIy cIose approximation to a nutrient capiIIary. (Fig. I.) However, in the presence of a massive increase in interstitia1 ffuid in the form of edema, the

With the partia1 soIution of many probIems associated with occIusive disease of the Iarge arteries, more attention is being accorded the bIood ffow through the arterioIes, capiIIaries and venuIes. CircuIation through these smaIIest vesseIs, which actuaIIy convey oxygen to the environs of tissue ceIIs, may be defective from a variety of causes. First, small vesseIs may have been obIiterated by a disease process. Second, sIudging may or may not be deIeterious. Third, diffuse thrombosis of the smaIIest vesseIs during a period of hypotension has been shown by CroweII and Smith [29] to be one factor which may render shock irreversible. In fact, in experimenta transpIantation of the heart, it is usefu1 either to flush out a11 bIood from the coronary vesseIs or 487

Hardy

FIG. IO. Gangrene of fingers due to thrombosis of Ieft innominate vein. A MongoIian idiot was admitted with an WhiIe thrombosis invoIving an iIiac vein or the advanced degree of tissue gangrene due to venous obstruction. vena cava rarely produces gangrene of the Ieg despite even extreme swelling, at times necrosis does occur. And even if major tissue death does not occur, prolonged venous or lymphatic stasis may result in skin atrophy and even ulceration.

celI-capiIIary distance would presumably increase. Therefore, the presence of marked edema of the lower extremities wouId be expected not onIy to impede the venous circuIation, but aIso to increase the distance which the oxygen must traveI from the red bIood ceI1, through the waI1 of the capiIIary, through the interstitia1 fluid, to the tissue ceI1. (Fig. I.) AIthough the extent to which such an increase in tissue fluid affects ceIIuIar metaboIism has not been fuIIy determined, there wouId appear to be IittIe doubt that the norma oxygenation of the tissue ceI1 wouId be interfered with by excessive deposits of interstitia1 fluid. Gangrene of the toes has been known to deveIop foIIowing cardiac faiIure with massive sweIIing of the legs, though perhaps some of the extremities had aIready been compromised by atheroscIerotic deposits. LYMPHATIC

SYSTEM

The importance of Iymphatic ffow and its relation to the mechanics of venous fIow is accepted. However, the precise ways in which

impaired Iymphatic flow contributes to tissue hypoxia have yet to be cIearIy defined. THE

INTERSTITIAL

AND

INTRACELLULAR

FLUIDS

Hypoxia at the Cellular Level. UItimateIy, it is hypoxia at the ceIIuIar IeveI which may resuIt in the irreversibIe changes that terminate in death. It may be seen in Figure I that the ceI1 and its components must secure oxygen from the surrounding tissue &id, whose oxygen content may be influenced by muItipIe factors previousIy described. In some manner, the oxygen needs of the ceI1 are thought to reguIate the bIood ffow to the tissue invoIved. This autoreguIation of bIood flow by oxygen Iack of specific tissues has been the subject of extensive investigation. The genera1 thesis is that hypoxia resuIts in vasodiIatation due to the fact that the ceIIs surrounding the vesse1 are in competition with the smooth muscIe of the vesse1 waI1 for oxygen. If the tissue shouId use most of the avaiIabIe oxygen, the vesseIs wouId diIate because the smooth muscIe ceIIs of the vesse1 waIIs wouId have insuffrcient oxygen to

Tissue

Hypoxia

in SurgicaI

maintain contraction. Ross et a1. [31] beIieve that the increased bIood flow which follows temporary hypoxia of a given tissue resuIts from a simple Iack of oxygen and not from the reIease of a vasodilator substance. RegardIess of the nature of the precise mechanism through which hypoxia at the tissue IeveI resuIts in an increased blood flow to that tissue, there appears to be IittIe doubt that some such mechanism is an important factor in preventing hypoxia in, for exampIe, muscIes which have been severeIy exercised. Within the ceI1 itself, there is evidence that hypoxia may inffuence the subsequent uptake of IabeIIed carbon atoms by various components of the cell. (Fig. II.) Thus, effects of hypoxia upon the metaboIism not onIy of the ceII but of its component parts is a matter of current research interest in our Iaboratory. TheoreticaIIy, severe hypoxia of the ceI1 and the subceIIuIar fractions might produce molecuIar damage which couId resuIt in subsequent inability of these ceIIs to demand more bIood from the nutrient vesseIs, even after resuscitation therapy had improved cardiac output. The finite mechanisms by which oxygen requirements are met in the presence of hyperthermia and reduced in hypothermia stand as chaIIenges to further investigation.

/

Practice

L

I--Mitochondrio

FIG. I I. The ceII and subceIIuIar components. Much research interest is being directed to factors which may affect celI “respiration”and the oxidative processes of subceIIuIar particIes. There is evidence that a period of hypoxia may aIter to varying degrees the subsequent metabolic activity of one subcellular fraction as compared with another.

management of hypoxia requires a comprehensive awareness of the many different pathoIogic conditions which may resuIt in hypoxia at the tissue IeveI. WhiIe admittedIy the factors which influence the efficiency with which the component parts of the ceI1 utiIize oxygen to perform their respective biochemica1 processes must await further study, there is much that can be done to combat hypoxia of the cells of various organs. This is accompIished through improvement of the various components of respiration, by correcting Iesions of the heart and of the aorta and its branches, by preventing hypotension through maintaining a quantitatively and quaIitativeIy adequate circuIating blood voIume and periphera1 resistance, and by being aware of specific probIems of thrombosis in the smaIIer arteries and the microcirculation, where increasingIy appreciated rheoIogic factors are of much importance.

SUMMARY

The prevention and treatment of hypoxia embraces a considerabIe segment of surgicaI practice. The hypoxia may be acute or chronic and may be produced through a variety of mechanisms. These invoIve abnormalities of respiration, heart action, brood voIume and bIood composition. There may exist occIusive disease of Iarger arteries, or excessive or inadequate constriction of the arterioles, leading to hypoxia either from spasm or from Iack of periphera1 resistance to maintain an adequate systemic arteria1 blood pressure. There may deveIop defective flow through eIements of the microcircuIation, as we11 as defective oxygen utiIization by the ceI1 and the subceIIuIar fractions. Increased interstitia1 ffuid, the resuIt of Iymphatic or venous stasis, may aIso resuIt in hypoxia and abnorma1 metabolism at the ceIIuIar IeveI. Hypoxia uItimateIy resuIts in disintegration of the ceIIuIar processes, due in part to the resuIting metabolic acidosis, with eventua1 death of the tissue. The consistentIy effective prevention and

REFERENCES

I. LORINCZ, A. L., JACOBY, J. J. and LIVINGSTONE, H. M. Studies on the oarenteral administration of hydrogen peroxide: Anesthesiology, g: 162, 1948. 2. BOEREMA, I. An operating room with high atmospheric pressure. Surgery, 49: zgr, 1960. 3. COOLEY, D. A., BEALL, A. C., JR. and ALEXANDER,

489

Hardy

4.

5.

6.

7.

8.

g.

10.

I I.

12.

13.

14.

15.

.I. K. Acute massive pulmonary embolism; successfut surgical treatment using temporary CardiopuImonary bypass. J. A. M. A., 177: 283, rg6r. RADIGAN, L. R. and KING, R. D. A technique for ateIectasis. the prevention of postoperative Surgery, 47: 184, 1960. WEBB, W. R. Clinical evaluation of a new mucoIytic agent, acetyIcysteine. J. Tbor. Cardiov. Surg., 44: 330, 1962. THUNG. N.. DAMMANN. J. F.. JR.. DIAZ-PEREZ, R.. THO~PS&, W. M., JR., S~NM~RCO, M. and ME: HEGAN, C. Hypoxia as the cause of hemorrhage into the cardiac conduction system, arrhythmia and sudden death. J. Tbor. Cardiov. Surg., 44: 687, 1962. COTTON, R. T. and BEDFORD, D. R. Symmetrica periphera1 gangrene compIicating acute myocardia1 infarction. Am. J. Med., 20: 301, 1956. HOFFMAN, F. G., ZIMMERMAN,S. L. and CARDWELL, E. S., JR. Massive intestina1 infarction without vascular occIusion associated with aortic insuffrciency. New England J. Med., 263: 436, 1960. JACOBSON,L. O., GOLDWASSER,E., GURNEY, C. W., FRIED, W. and PLZAK, L. Studies of erythropoietin: the hormone regulating red ceI1 production. Ann. New York Acad. SC., 77: 551, 1959. HARDY, J. D. and DRABKIN, D. L. Measurement of body water; techniques and practica1 implications. J. A. M. A., 149: 1113, 1952. DALTON, M. L., JR., TYLER, H. and HARDY, J. D. Use of packed red ceIIs versus whoIe bIood in the presence of impaired cardiac reserve. Surg. Gynec. @ Obst., I I I : 729, 1960. WILLIAMS, J. A. and FINE, J. Measurement of bIood voIume with a new apparatus. New England J. Med., 264: 842, 1961. ELKINTON, J. R., DANOWSKI, T. S. and WINKLER, A. W. Hemodynamic changes in salt depIetion in dehydration. J. Clin. Invest., 25: 120, 1946. HOPPER, J., JR., ELKINTON, J. R. and WINKLER, A. W. Plasma voIumes of dogs in dehydration with and without saIt 10s~. J. Clin. Invest., 23: III,I944. HUTCHINSON, J. H. and HOWELL, R. A. CryogIobuIinemia: report of case associated with gangrene of the digits. Ann. Znt. Med., 39: 350,

1953. 16. JAGER, B. V. Cryofibrinogenemia. New England J. Med., 266: 579, 1962. 17. LIECHTY, R. D., IOB, V. and MCMATH, M. Cryoproteinemia: its reIationship to periphera1 vascular disease. Ann. Surg., SuppI. 154: 319, 1961.

490

18. WEBB, W. R. Persona1 communication. rg. ADKINS, J. R., MILLER, T. I., CARTER, T. and HARDY, J. D. The hormona1 mediation of neurovascuIar reflex adjustments: catecho amine response to postura1 changes in man. Am. Surgeon, 27: 210, rg6r. 20. VON EULER, U. S. and FRANKSSON, C. Increase in noradrenaline excretion foIlowing activation of the vasomotor system during tiIting in adrenaIectomized patients. Acta pbysiol. scandinav., 38: 285, 1957. 21. HICKLER, R. B., WELLS, R. E., JR., TYLER, H. R. and HAMLIN, J. T., III. PIasma catecho amine and eIectroencephaIographic responses to acute postura1 change: evidence of a dehcient pressor amine response in postura1 hypotension. Am. J. Med., 26: 410, 1959. 22. BROWN, R. B. and BAROWSKY, M. Further observations on intestina1 Iesions associated with pheochromocytomas. Ann. Surg., 151: 683, 1960. 23. HARDY, J. D. and ALICAN, F. Ischemic gangrene without major organic vascuIar occIusion: an enIarging concept. Surgery, 50: 107, rg6r. 24. BURCH, G. E. and DEPASQUALE, N. P. Hematocrit, blood viscosity and myocardial infarction. Edit. Am. J. Med., 32: 161, 1962. 25. WELLS, R. E., JR. and MERRILL, E. W. Shear rate dependence of the viscosity of whoIe bIood and pIasma. Science, 133: 763, 1961. 26. WELLS, R. E., JR. and MERRILL, E. W. The variability of bIood viscosity. Edit. Am. J. Med., 31: 505, 1961. 27. BURCH. G. E. and DEPASOUALE. N. P. The hematocrit in patients with myocardia1 infarction. J. A. M. A., 180: 63, 1962. 28. HARDY, J. D. and ROBINSON, S. L. Disappearing foot puIses; case cured by iIiac endarterectomy with comments on ffow mechanisms. Ann. Surg., 156: 776, 1962. 29. CROWELL, J. W. and SMITH, E. E. Effect of fibrinoIytic activation on surviva1 and cerebra1 damage foIlowing periods of circuIatory arrest. Am. J. Pbysiol., 186: 283, 1956. 30. WEBB, W. R. and HOWARD, H. S. Extensions of the Iimits of cardiac viabiIity with tota coronary 0ccIusion. Surgery, 42: 92, 1957. 31. Ross, J. M., FAIRCHILD, H. M., WELDY, J. and GUYTON, A. C. AutoreguIation of bIood Aow by oxygen Iack. Am. J. Pbysiol., 202: 21, 1962. 32. RODMAN, T., CLOSE, H. P., CATHCART, R. and PURCELL, M. K. The oxyhemogIobin dissociation curve in the common hemogIobinopathies. Am. J. Med., 27: 558, 1959. I