WO1997012627A1 - Therapeutic administration of hemoglobin in cardiac arrest - Google Patents

Therapeutic administration of hemoglobin in cardiac arrest Download PDF

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Publication number
WO1997012627A1
WO1997012627A1 PCT/US1996/013512 US9613512W WO9712627A1 WO 1997012627 A1 WO1997012627 A1 WO 1997012627A1 US 9613512 W US9613512 W US 9613512W WO 9712627 A1 WO9712627 A1 WO 9712627A1
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Prior art keywords
hemoglobin
stroma
free hemoglobin
modified
chemically
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PCT/US1996/013512
Other languages
French (fr)
Inventor
Kenneth E. Burhop
Moses S. S. Chow
Original Assignee
Baxter International Inc.
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Publication date
Application filed by Baxter International Inc. filed Critical Baxter International Inc.
Priority to AU68531/96A priority Critical patent/AU710496B2/en
Priority to EP96928960A priority patent/EP0853485A4/en
Priority to JP9514246A priority patent/JPH11512738A/en
Publication of WO1997012627A1 publication Critical patent/WO1997012627A1/en
Priority to NO981564A priority patent/NO981564L/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/41—Porphyrin- or corrin-ring-containing peptides
    • A61K38/42—Haemoglobins; Myoglobins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives

Definitions

  • Cardiac arrest is a desperate clinical event in which the heart ceases its normal pumping action and devolves into ventricular fibrillation. Unless spontaneous circulation is restored, death from anoxia is rapid.
  • the treatment for cardiac arrest is now standardized in the Handbook for Adult and Pediatric Providers, "Advanced Cardiac Life Support: Algorithms and Drugs", American Heart Association, reproduced from JAMA. 268: 2155 (1992), which sets out in detail the recommended procedures for administration of drugs and physical intervention in cardiopulmonary resuscitation (CPR) .
  • CPR cardiopulmonary resuscitation
  • the present invention provides a method of treatment tor improving return of spontaneous circulation during CPR attending cardiac arrest.
  • Return of spontaneous circulation or alternatively termed, successful resuscitation, is defined as an organized rhythm with an unassisted systolic blood pressure of greater than 60 mm Hg for a period equal to or greater than 2 minutes.
  • stroma-free chemically crosslinked, conjugated, or polymerized hemoglobin is administered during ventricular fibrillation in a dose ranging from 50 to 2500 mg per kg of body weight, while simultaneously performing standard cardiopulmonary resuscitation (CPR) procedures, and then defibrillating electrically to effect return of spontaneous circulation.
  • CPR cardiopulmonary resuscitation
  • CPR includes specifically chest compression which is a procedure for mechanically compressing the thoracic walls to contract and expand the blood volume contained in the heart. This normal working of the heart valves prevents backflow of blood which is expelled during the compres ⁇ ion step, thereby simulating blood circulation while the heart is unable to sustain regulated contractions on its own.
  • Figure 1 is a diagram illustrating the experimental protocol set forth in the Example.
  • the administration of hemoglobin by infusion is intended to augment rather than contravene the standard CPR measures established by the American Heart Association in its Advanced Cardiac Life Support Handbook, supra.
  • Infusion of hemoglobin should be instituted immediately upon determination of cardiac arrest. A ⁇ a practical matter, at least several minutes may lapse before a correct diagnosis is made. Since the hemoglobin is understood to act at least in part by increasing tissue perfusion, it is important that contact between the blood-borne hemoglobin and important tissues of the heart and brain be made quickly. The other mechanical and pharmaceutical interventions of CPR are carried out simultaneously.
  • Spontaneou ⁇ circulation means a correction of ineffectual fibrillation to ventricular contraction effective for displacing blood contained in the heart chamber to the aorta with regular sinus rhythm.
  • Many of the drugs used in connection with cardiac arrest have the properties of helping to establish and maintain this action, and to suppres ⁇ arrhythmia ⁇ .
  • the mechanisms by which these drugs act have in some cases been at least partially elucidated.
  • the mechanism of the present invention involving infusion of hemoglobin is unknown, but the administration of hemoglobin during CPR ⁇ ignificantly improves return of spontaneous circulation.
  • the hemoglobin utilized in the present invention may be of any type which is stroma-free and modified chemically to prevent subunit dis ⁇ ociation and to increase the oxygen binding affinity to the range of P 50 values between about 20 and 45 mm Hg.
  • the modified hemoglobin may be a conjugated hemoglobin, crosslinked hemoglobin,or polymerized hemoglobin.
  • a conjugated hemoglobin is one to which a non- protein macromolecule is bound covalently to hemoglobin.
  • a hemoglobin chemical modified by poly-alkylene glycol which is described together with a proces ⁇ for its preparation in WO 91/07190 (Enzon) .
  • Hemoglobin conjugated to poly(alkylene oxide) and a process for its preparation i ⁇ provided in U.S. Patent No ⁇ . 4,301,144, 4,412,989 and 4,670,417, and in Japanese Patent Nos. 59-104323 and 61-053223 (Ajinomoto) .
  • Hemoglobin may be conjugated to inulin in a proces ⁇ disclosed in U.S. Patent No. 4,377,512 (Ajinomoto) .
  • the patents WO 91/07190, U.S. Patent No ⁇ . 4,301,144, 4,670,412, 4,377,512 and Japanese Patent No ⁇ . 59- 104323 and 61-053223 are hereby incorporated by reference.
  • a crosslinked hemoglobin contains an intramolecular chemical link.
  • Example ⁇ of cro ⁇ linked hemoglobin ⁇ and method ⁇ for their preparation are described in U.S. Patent Nos. 4,001,401 and 4,053,590, which disclose intramolecular cros ⁇ linking between an alpha and beta subunit of a hemoglobin tetramer utilizing compounds such as halogenated cycloalkanes, diepoxide ⁇ , and diazobenzidines.
  • a preferred modified hemoglobin is cros ⁇ linked with bi ⁇ (3, 5-dibromo ⁇ alicyl) fumarate to create a fumarate crosslink between the two alpha subunits.
  • DCLHb The preferred diaspirin cro ⁇ linked hemoglobin will hereafter be referred to as "DCLHb" .
  • a polymerized hemoglobin is one in which intermolecular cros ⁇ -linking of hemoglobin tetramer ⁇ has been used to increase the molecular weight of the modified hemoglobin.
  • An example of a polymerized hemoglobin and a process for its preparation are described in U.S. pending applications Serial Nos. 08/149,679, 08/173,882, 08/480,593 and 08/473,459.
  • U.S. Patent No. 4,777,244 discloses a method for crosslinking and polymerizing with aliphatic dialdehydes. The foregoing patent ⁇ are hereby incorporated by reference.
  • U.S. Patent No. 5,248,766 discloses a crosslinking polymerizing strategy and a proces ⁇ for covalently interconnecting tetrameric units with oxiranes to form polyhemoglobins with molecular weights in excess of 120,000 Daltons.
  • Hemoglobin may be modified by site-directed mutagenesi ⁇ and expre ⁇ ed in micro-organi ⁇ ms or transgenic animal ⁇ . Recombinant mutant and artificial hemoglobin and its production in cell cultures or fluids is described in U.S. Patent 5,028,588 (Somatogen) . Di-alpha and di-beta globin-like polypeptide(s) used for production of hemoglobin in bacteria and yeast are described in WO 90/13645 (Somatogen) .
  • a non-natural multimeric hemoglobin-like protein is described in WO 93/09143 (Somatogen) .
  • any method of crosslinking, polymerizing, encapsulating or genetically modifying, or combination thereof which yields a free tetramer having a P50 in the operative range of 20 to 45 mm Hg will have efficacy in the present method.
  • Condition ⁇ may be adjusted for each ⁇ uch cro ⁇ slinked tetramer or polymer derived therefrom without undue experimentation.
  • the dosage of hemoglobin administered in the present method may vary over a range of 50 to 2500 mg per kg of body weight . Larger doses may be indicated in situations where return to spontaneous circulation is more protracted or difficult, or where restored circulation is unstable. Dosage is also influenced by the type and dose of other drugs administered simultaneously or in sequence post-cardiac arrest. In general, repeat treatment after return of spontaneou ⁇ circulation i ⁇ unneces ⁇ ary, unle ⁇ s another episode of cardiac arrest occurs.
  • hemoglobin therapy Another benefit of hemoglobin therapy is increased perfusion to the brain.
  • the use of hemoglobin to enhance perfusion and minimize brain cell damage thus has a secondary advantage. Other advantages will be apparent from the Example which follows.
  • VF Ventricular fibrillation
  • the pigs were paced from the right ventricular apex as a rate of 200 to 235 bpm for eight beats using a current equal to twice the pacing threshold.
  • the intensity of the electrical ⁇ timulus wa ⁇ increased in 2 mA increments until VF developed.
  • ventilation wa ⁇ ⁇ topped for five minutes.
  • cardiopulmonary re ⁇ u ⁇ citation (CPR) was started using a pneumatic chest compression device (Thumper) .
  • the thumper was set at 80 compressions per minute with a force sufficient to achieve an aortic blood pressure of 50 to 65 mm HG.
  • diastole was prolonged by 0.5 second ⁇ and the lung ⁇ inflated to an inspiratory pressure of approximately 20 cm H 2 0 by a synchronized pressure limited ventilator with room air.
  • the CPR was stopped at 15 minutes and followed with external defibrillation which was attempted at 200J. If needed, the shocks were repeated at 3OOJ and then at 360J until sinus rhythm (SR) was restored. If the pigs could not achieve or maintain a blood pre ⁇ ure > 60 mm Hg with organized ⁇ inus rhythm, 100% oxygen was added and epinephrine.
  • lidocaine or atropine were administered according to the American Heart As ⁇ ociation (AHA) and Advanced Cardiac Life Support (ACLS) guidelines.
  • Successful resuscitation was defined as return of spontaneous circulation (ROSC) post-defibrillation with a blood pressure > 60 mm Hg for at least two minutes with or without additional 0 2 or drugs ( ⁇ ee protocol shown in Figure 1) .
  • ROSC spontaneous circulation
  • Blood samples were collected at baseline, and then at 11 minutes, and 14 minutes post-induction of ventricular fibrillation (corresponding to 6 and 9 minutes of initiation of CPR) from the femoral artery, internal jugular vein, and pulmonary artery for measurement of blood gases (238 pH blood gas analyzer, Ciba Corning, MA) , lactate concentration (ultraviolet method, Sigma Chemical Co., St. Louis, MO), hemoglobin concentration (coulter counter method) , and hematocrit (coulter counter method) .
  • blood gases (238 pH blood gas analyzer, Ciba Corning, MA)
  • lactate concentration ultraviolet method
  • Sigma Chemical Co. St. Louis, MO
  • hemoglobin concentration coulter counter method
  • hematocrit coulter counter method
  • the colored micro ⁇ phere ⁇ were injected into the left ventricle at ba ⁇ eline and during CPR.
  • the blood ⁇ ample ⁇ were collected over two minutes for the calculation of total cardiac output.
  • Organ sample ⁇ were collected at the end of the experiment for mea ⁇ uring of organ blood flow.
  • Aortic, left ventricular, and pulmonary artery pressure were monitored during the study and recorded at 0, 6, 9, 12, 14 minutes of fibrillation (see protocol shown in Figure 1) .
  • DCLHb or normal saline (control treatment) were infused over a 5 minute time interval in a random and blinded manner.
  • the total dose of DCLHb or normal saline administered in each animal was either 5 ml/kg or 15 ml/kg. All animals al ⁇ o received sodium bicarbonate infu ⁇ ion at 0.1 meg/kg/min at the beginning of CPR to decrease development of acidosis (see protocol shown in Figure 1) .
  • Two pigs in the control group (saline treatment) compared to 6 in the DCLHb group achieved a return of spontaneous circulation (ROSC; p ⁇ 0.05) at the end of 15 minutes of VF following defibrillation (see Figure 1) .
  • # Shock number of DC shocks delivered to achieve defibrillation
  • the mean blood gases obtained at arterial (from aorta), venous (from pulmonary artery), and internal jugular venous sites are summarized in Table 2.
  • Significantly better venous pH, venous pC0 2 were observed in the DCLHb treatment group compared to the control group.
  • the mean 0 2 content is also summarized as shown in Table 3. Significantly high venous 0 2 content were observed in the DCLHb treatment group compared to the rontro] group.
  • the mean blood pressures at different sites are summarized in Table 4. Significantly higher cerebral perfusion pressures (CePP) were observed in the DCLHb group compared to the control group (p ⁇ 0.05) . Although not statistically significantly different, other mean systolic and diastolic pressures were generally higher in the DCLHb group. A decrease in coronary perfusion pressure (CoPP) at 14 minutes compared to 6 minutes (beginning of CPR) were observed in 6 of 8 control animals as compared to 2 of 8 DCLHb treatment animals (p ⁇ 0.05) .
  • CoPP coronary perfusion pressure
  • the total cardiac output, myocardial blood flow, and cerebral blood flow during normal ⁇ inu ⁇ rhythm (ba ⁇ eline) and CPR in the two group ⁇ are shown in Tables 5, 6, and 7.
  • the mean cardiac output during CPR ranged from 17-21% of baseline, whereas the mean cerebral blood flow during CPR ranged 48 to 78% of baseline, indicating a preferential shunting of flow to the brain during CPR.
  • the mean myocardial flow during CPR ranged only 7-10% of baseline, indicating the critical nature of the myocardium during CPR. There was a trend toward higher myocardial flow during CPR in the DCLHb group, however no statistically significant difference was observed for all flow parameter ⁇ between the 2 group ⁇ due to large variability observed in these measured values.
  • DCLHb treatment ⁇ ignificantly improved resuscitation (great ROSC at the end of CPR) as compared to saline treatment.
  • This improved resuscitation in the DCLHb group is accompanied by significantly better venous 0 2 content and le ⁇ s coronary perfusion pressure deterioration.
  • DCLHb appeared to improve resuscitation post- cardiac arrest and CPR in this animal model .
  • the beneficial effect of DCLHb may be related to improved oxygen delivery during CPR.
  • A-arterial sample from aorta V-venous sample, IJ-internal jugular vein sample.

Abstract

Administration of stroma-free cross-linked hemoglobin during standard cardiac pulmonary resuscitation procedures enhances return of spontaneous circulation following electrical defibrillation. The difficulty in restoring spontaneous circulation directly correlates with a generally poor prognosis in cases of cardiac arrest. The therapeutic effect of hemoglobin as an adjunct to conventional treatment may thereby improve survival.

Description

THERAPEUTIC ADMINISTRATION OF HEMOGLOBIN IN
CARDIAC ARREST
Background of the Invention Cardiac arrest is a desperate clinical event in which the heart ceases its normal pumping action and devolves into ventricular fibrillation. Unless spontaneous circulation is restored, death from anoxia is rapid. The treatment for cardiac arrest is now standardized in the Handbook for Adult and Pediatric Providers, "Advanced Cardiac Life Support: Algorithms and Drugs", American Heart Association, reproduced from JAMA. 268: 2155 (1992), which sets out in detail the recommended procedures for administration of drugs and physical intervention in cardiopulmonary resuscitation (CPR) .
These procedures call for opening an adequate airway to the patient, providing positive-pressure ventilation, giving chest compressions, and inducing defibrillation. These procedures are supported.by administration of appropriate drugs. The Handbook referred to above lists the drugs and provides detailed instructions for their respective indications and recommended dosages. In addition there have been many experimental studies in which various drugs have been evaluated. For example, Capparelli, et al . , Crit. Care Med.. 20: 1140 (1992) describes improved resuscitation in dogs undergoing cardiac arrest upon treatment with diltiazem. Similarly, administration of lidocaine dramatically improved arterial pressure, left ventricular pressure and carotid blood flow in the dog model during cardiopulmonary resuscitation (See Chow, et al . , J. Pharm. and Exϋer. Ther.. 224: 531 [1983]) .
One of the consequences of cardiac arrest followed by CPR is venous acidosis. Bleske, et al. , Am. J. Emerσ. Med. , 10: 525 (1992) describes the administration of sodium bicarbonate during CPR to control acidosis. Because of the high incidence of mortality during cardiac arrest, even when the current CPR algorithms are adhered to, strategies for combination therapies are needed to improve patient survival.
Summary of the Invention
The present invention provides a method of treatment tor improving return of spontaneous circulation during CPR attending cardiac arrest. Return of spontaneous circulation, or alternatively termed, successful resuscitation, is defined as an organized rhythm with an unassisted systolic blood pressure of greater than 60 mm Hg for a period equal to or greater than 2 minutes. In the present method of resuscitating a mammal undergoing cardiac arrest, stroma-free chemically crosslinked, conjugated, or polymerized hemoglobin is administered during ventricular fibrillation in a dose ranging from 50 to 2500 mg per kg of body weight, while simultaneously performing standard cardiopulmonary resuscitation (CPR) procedures, and then defibrillating electrically to effect return of spontaneous circulation. CPR includes specifically chest compression which is a procedure for mechanically compressing the thoracic walls to contract and expand the blood volume contained in the heart. This normal working of the heart valves prevents backflow of blood which is expelled during the compresεion step, thereby simulating blood circulation while the heart is unable to sustain regulated contractions on its own.
It is also desirable to reduce or eliminate acidosis occurring during CPR. Coadministration of sodium bicarbonate solutions in a dose range of 0.01 to 1.0 meg per kg of body weight per minute during CPR is efficacious for this purpose. Other drugs such aε epinephrine, lidocaine or atropine may also be simultaneously administered in accordance with the Advanced Cardiac Life Support, guidelines, supra.
Brief Description of the Drawing
Figure 1 is a diagram illustrating the experimental protocol set forth in the Example.
Detailed Description of the Preferred Embodiment
In the present method, the administration of hemoglobin by infusion (intravenous or intraarterial infusion or cannulation) is intended to augment rather than contravene the standard CPR measures established by the American Heart Association in its Advanced Cardiac Life Support Handbook, supra. The same indications prompted by clinical observation should be adhered to as are recommended in the Handbook. Infusion of hemoglobin should be instituted immediately upon determination of cardiac arrest. Aε a practical matter, at least several minutes may lapse before a correct diagnosis is made. Since the hemoglobin is understood to act at least in part by increasing tissue perfusion, it is important that contact between the blood-borne hemoglobin and important tissues of the heart and brain be made quickly. The other mechanical and pharmaceutical interventions of CPR are carried out simultaneously.
In resuscitation of patients undergoing cardiac arrest, there is a necessary correlation between return of spontaneous circulation and successful resuscitation, since restoration of normal pumping action must occur if the heart iε to εurvive. Spontaneouε circulation means a correction of ineffectual fibrillation to ventricular contraction effective for displacing blood contained in the heart chamber to the aorta with regular sinus rhythm. Many of the drugs used in connection with cardiac arrest have the properties of helping to establish and maintain this action, and to suppresε arrhythmiaε. The mechanisms by which these drugs act have in some cases been at least partially elucidated. The mechanism of the present invention involving infusion of hemoglobin is unknown, but the administration of hemoglobin during CPR εignificantly improves return of spontaneous circulation.
The hemoglobin utilized in the present invention may be of any type which is stroma-free and modified chemically to prevent subunit disεociation and to increase the oxygen binding affinity to the range of P50 values between about 20 and 45 mm Hg. The modified hemoglobin may be a conjugated hemoglobin, crosslinked hemoglobin,or polymerized hemoglobin.
Several examples of hemoglobin modification technology have been described in the scientific literature which may be used to advantage in the practice of the present invention. For example, see the review contained in Winslow, R.M. , Hemoαlobin- baεed Red Cell Substitutes, The John Hopkins U. Preεε (1992) . More specifically, the methods of making chemically modified hemoglobin are set forth hereinafter. A conjugated hemoglobin is one to which a non- protein macromolecule is bound covalently to hemoglobin. One example is a hemoglobin chemical modified by poly-alkylene glycol, which is described together with a procesε for its preparation in WO 91/07190 (Enzon) . An example of a hemoglobin conjugated to poly(alkylene oxide) and a process for its preparation iε provided in U.S. Patent Noε. 4,301,144, 4,412,989 and 4,670,417, and in Japanese Patent Nos. 59-104323 and 61-053223 (Ajinomoto) . Hemoglobin may be conjugated to inulin in a procesε disclosed in U.S. Patent No. 4,377,512 (Ajinomoto) . The patents WO 91/07190, U.S. Patent Noε. 4,301,144, 4,670,412, 4,377,512 and Japanese Patent Noε. 59- 104323 and 61-053223 are hereby incorporated by reference. A crosslinked hemoglobin contains an intramolecular chemical link. Exampleε of croεεlinked hemoglobinε and methodε for their preparation are described in U.S. Patent Nos. 4,001,401 and 4,053,590, which disclose intramolecular crosεlinking between an alpha and beta subunit of a hemoglobin tetramer utilizing compounds such as halogenated cycloalkanes, diepoxideε, and diazobenzidines. In the present method, a preferred modified hemoglobin is crosεlinked with biε (3, 5-dibromoεalicyl) fumarate to create a fumarate crosslink between the two alpha subunits.
This crosslinked hemoglobin is more fully described, together with methods for its preparation, in U.S. Patent Noε. 4,598,064, 4,600,531, RE 34,271, omitting the chromatography εtep. It iε preferably manufactured under the conditionε diεcloεed in U.S. Patent No. 5,128,452 (Hai) to prevent crosεlinking between β chainε. U.S. Patent Nos. 4,598,064, 4,600,531, RE 34,271 and 5,128,452 are hereby incorporated by reference. WO 90/13309 (Staat Der Nederlanden De Miniεter Van Defeuric) discloseε a method for crosslinking hemoglobin through a β-β linkage. The preferred diaspirin croεεlinked hemoglobin will hereafter be referred to as "DCLHb" . A polymerized hemoglobin is one in which intermolecular crosε-linking of hemoglobin tetramerε has been used to increase the molecular weight of the modified hemoglobin. An example of a polymerized hemoglobin and a process for its preparation are described in U.S. pending applications Serial Nos. 08/149,679, 08/173,882, 08/480,593 and 08/473,459. U.S. Patent No. 4,777,244 discloses a method for crosslinking and polymerizing with aliphatic dialdehydes. The foregoing patentε are hereby incorporated by reference. A hemoglobin that haε been modified by a combination of methods iε exemplified by the following. Hemoglobins modified by pyridoxal-5' - phoεphate to adjuεt the oxygen affinity and by polyethylene glycol conjugation and procesεes for its preparation are described in Japanese Patent Nos. 59- 089629, 59-103322 and 59-104323 (Ajinomoto) . U.S. Patent No. 5,248,766 discloses a crosslinking polymerizing strategy and a procesε for covalently interconnecting tetrameric units with oxiranes to form polyhemoglobins with molecular weights in excess of 120,000 Daltons. The foregoing patentε disclosing polymerized hemoglobins, U.S. Patent Nos. 5,194,590, 5,248,766, Japanese Patent Nos. 59-103322, 59-089629 and 59-104323, are hereby incorporated by reference. Hemoglobin may be modified by site-directed mutagenesiε and expreεεed in micro-organiεms or transgenic animalε. Recombinant mutant and artificial hemoglobin and its production in cell cultures or fluids is described in U.S. Patent 5,028,588 (Somatogen) . Di-alpha and di-beta globin-like polypeptide(s) used for production of hemoglobin in bacteria and yeast are described in WO 90/13645 (Somatogen) . A non-natural multimeric hemoglobin-like protein is described in WO 93/09143 (Somatogen) . In general any method of crosslinking, polymerizing, encapsulating or genetically modifying, or combination thereof which yields a free tetramer having a P50 in the operative range of 20 to 45 mm Hg will have efficacy in the present method. Conditionε may be adjusted for each εuch croεslinked tetramer or polymer derived therefrom without undue experimentation. The dosage of hemoglobin administered in the present method may vary over a range of 50 to 2500 mg per kg of body weight . Larger doses may be indicated in situations where return to spontaneous circulation is more protracted or difficult, or where restored circulation is unstable. Dosage is also influenced by the type and dose of other drugs administered simultaneously or in sequence post-cardiac arrest. In general, repeat treatment after return of spontaneouε circulation iε unnecesεary, unleεs another episode of cardiac arrest occurs.
Another benefit of hemoglobin therapy is increased perfusion to the brain. One problem in resuεcitation from cardiac arrest, is the losε of blood flow to the brain resulting in ischemia and brain damage. It is possible that succeεsful resuscitation will only result in an incurable vegetative state. The use of hemoglobin to enhance perfusion and minimize brain cell damage thus has a secondary advantage. Other advantages will be apparent from the Example which follows.
Example
Ventricular fibrillation (VF) was induced by direct current stimulation to the right ventricle of teεt pigs. The pigs were paced from the right ventricular apex as a rate of 200 to 235 bpm for eight beats using a current equal to twice the pacing threshold. The intensity of the electrical εtimulus waε increased in 2 mA increments until VF developed. After the induction of VF, ventilation waε εtopped for five minutes. Then, cardiopulmonary reεuεcitation (CPR) was started using a pneumatic chest compression device (Thumper) . The thumper was set at 80 compressions per minute with a force sufficient to achieve an aortic blood pressure of 50 to 65 mm HG. After five compresεionε, diastole was prolonged by 0.5 secondε and the lungε inflated to an inspiratory pressure of approximately 20 cm H20 by a synchronized pressure limited ventilator with room air. The CPR was stopped at 15 minutes and followed with external defibrillation which was attempted at 200J. If needed, the shocks were repeated at 3OOJ and then at 360J until sinus rhythm (SR) was restored. If the pigs could not achieve or maintain a blood preεεure > 60 mm Hg with organized εinus rhythm, 100% oxygen was added and epinephrine. lidocaine or atropine were administered according to the American Heart Asεociation (AHA) and Advanced Cardiac Life Support (ACLS) guidelines. Successful resuscitation was defined as return of spontaneous circulation (ROSC) post-defibrillation with a blood pressure > 60 mm Hg for at least two minutes with or without additional 02 or drugs (εee protocol shown in Figure 1) .
Blood samples were collected at baseline, and then at 11 minutes, and 14 minutes post-induction of ventricular fibrillation (corresponding to 6 and 9 minutes of initiation of CPR) from the femoral artery, internal jugular vein, and pulmonary artery for measurement of blood gases (238 pH blood gas analyzer, Ciba Corning, MA) , lactate concentration (ultraviolet method, Sigma Chemical Co., St. Louis, MO), hemoglobin concentration (coulter counter method) , and hematocrit (coulter counter method) .
The colored microεphereε were injected into the left ventricle at baεeline and during CPR. The blood εampleε were collected over two minutes for the calculation of total cardiac output. Organ sampleε were collected at the end of the experiment for meaεuring of organ blood flow. Aortic, left ventricular, and pulmonary artery pressure were monitored during the study and recorded at 0, 6, 9, 12, 14 minutes of fibrillation (see protocol shown in Figure 1) . One minute after the initiation of CPR (t=6 minutes of ventricular fibrillation) , DCLHb or normal saline (control treatment) were infused over a 5 minute time interval in a random and blinded manner. The total dose of DCLHb or normal saline administered in each animal was either 5 ml/kg or 15 ml/kg. All animals alεo received sodium bicarbonate infuεion at 0.1 meg/kg/min at the beginning of CPR to decrease development of acidosis (see protocol shown in Figure 1) . The outcome of the treatment iε shown in Table 1. Two pigs in the control group (saline treatment) compared to 6 in the DCLHb group achieved a return of spontaneous circulation (ROSC; p<0.05) at the end of 15 minutes of VF following defibrillation (see Figure 1) .
Table 1. Return of Spontaneous Circulation (ROSC) Post-CPR
Control
Pressure
(mm Hg)
Pig # LV A PA Drug # Shock ROSC*
14 132/0 97/59 29/9 YES 1 YES
20 66/0 54/10 33/10 YES 3 YES
3 YES 3 NO
6 YES 3 NO
8 YES 3 NO
11 YES 3 NO
12 YES 3 NO
16 YES 3 NO
DCLHb
Pressure
(mm Hg)
Pig # LV A PA Drug # Shock ROSC*
2 94/75 NO 1 YES
5 68/4 74/26 62/12 YES 2 YES
13 88/11 83/59 15/8 YES 2 YES
15 90/4 80/48 15/5 YES 3 YES
17 92/9 86/71 37/5 NO 1 YES
21 80/1 74/21 YES 1 YES
4 YES 3 NO
9 YES 3 NO
*p<0.05 (control vs. DCLHb using Chi Square analysis) Abbreviations: LV - left ventricular; PA - pulmonary artery; A - aortic. Drug: either of epinephrine, lidocaine or atropine used during ACLS
# Shock: number of DC shocks delivered to achieve defibrillation The mean blood gases obtained at arterial (from aorta), venous (from pulmonary artery), and internal jugular venous sites are summarized in Table 2. Significantly better venous pH, venous pC02 were observed in the DCLHb treatment group compared to the control group.
The mean 02 content is also summarized as shown in Table 3. Significantly high venous 02 content were observed in the DCLHb treatment group compared to the rontro] group.
The mean blood pressures at different sites are summarized in Table 4. Significantly higher cerebral perfusion pressures (CePP) were observed in the DCLHb group compared to the control group (p<0.05) . Although not statistically significantly different, other mean systolic and diastolic pressures were generally higher in the DCLHb group. A decrease in coronary perfusion pressure (CoPP) at 14 minutes compared to 6 minutes (beginning of CPR) were observed in 6 of 8 control animals as compared to 2 of 8 DCLHb treatment animals (p<0.05) .
The total cardiac output, myocardial blood flow, and cerebral blood flow during normal εinuε rhythm (baεeline) and CPR in the two groupε are shown in Tables 5, 6, and 7. The mean cardiac output during CPR ranged from 17-21% of baseline, whereas the mean cerebral blood flow during CPR ranged 48 to 78% of baseline, indicating a preferential shunting of flow to the brain during CPR. The mean myocardial flow during CPR ranged only 7-10% of baseline, indicating the critical nature of the myocardium during CPR. There was a trend toward higher myocardial flow during CPR in the DCLHb group, however no statistically significant difference was observed for all flow parameterε between the 2 groupε due to large variability observed in these measured values. In the present study of 16 immature pigs that suffered 5 minutes of fibrillation arrest followed by 10 minutes of CPR, DCLHb treatment εignificantly improved resuscitation (great ROSC at the end of CPR) as compared to saline treatment. This improved resuscitation in the DCLHb group is accompanied by significantly better venous 02 content and leεs coronary perfusion pressure deterioration.
Based upon the results obtained in the preεent study, DCLHb appeared to improve resuscitation post- cardiac arrest and CPR in this animal model . The beneficial effect of DCLHb may be related to improved oxygen delivery during CPR.
13
Table 2. Comparison of Mean Blood Gases, 02 Content/ Hemoglobin and Hematocrit
Control Group
Paramater Baseline 11 min 14 min pH(A) 7.41±0.03 7.3810.14 7.3610.18 pH(V) 7.37±0.04 7.0310.31* 7.0410.28* pH(IJ) 7.37±0.04 7.3010.18 7.3110.22 pC02(A) 41.1312.59 40.00111.99 43.25114.05 pCO,(V) 49.13±3.87 99.71144.56 92.50134.01* pC02IJ) 48.6318.45 68.00124.22 71.14136.88
0,sat (A) 96.0911.93 88.3017.07 87.0819.29
02sat (V) 77.73116.26 30.96114.91 31.00114.59
02sat (IJ) 79.51113.70 47.1719.80 43.60110.11 p02(A) 90.13122.62 62.00114.79 62.38114.84 p02(V) 47.25111.67 26.1414.18 25.5017.12 p02(IJ) 51.38115.46 31.7514.71 30.2915.22
0,content (A) 12.8010.83 11.8811.92 12.1711.94
0- content (V) 9.9812.72 3.4812.50* 3.6812.89
02content ( IJ) 10.7612.31 5.7712.81 5.2712.89 hemoglobi (A) 9.7810.79 9.8311.03 10.0511.01 hematocrit (A) 0.3310.02 0.3210.03 0.3310.02 hematocri (V) 0.3310.02 0.3310.04 0.3210.04 pC02(V) 49.13+3.87 99.71144.56 92.50134.01* hematocrit ( IJ) 0.3410.03 0.3210.06 0.3010.08
Table 2. (Cont'd)
DCLHb Group
Paramater Baseline 11 min 14 min pH(A) 7.4010.03 7.4110.10 7.4410.10 pH(V) 7.3710.04 7.2810.07 7.2710.07 pH(IJ) 7.3710.03 7.2910.11 7.2910.10 pC02(A) 42.6312.67 37.25110.42 36.83112.12 pC02(V) 46.3813.42 61.86120.22 57.13115.83 pCO.IJ) 48.6316.12 63.00113.39 64.38117.08
02sat (A) 96.4911.31 90.89+5.15 90.7714.41
02sat (V) 87.1113.52 46.40+15.23 43.60115.82
02sat ( IJ) 86.13113.34 52.66+21.77 50.60120.43
P02(A) 90.63116.39 63.00112.96 62.00117.99 p02(V) 55.7517.50 29.0016.72 28.00+6.35 p02(IJ) 55.88116.44 34.1318.32 31.6318.35
02content (A) 13.4410.62 13.7411.88 13.8711.91
02content (V) 12.0510.90 6.9912.73 6.6112.79
O2content ( IJ) 11.9111.85 7.8213.48 7.6413.41 hemoglobin (A) 10.1810.54 11.1110.98 10.9611.02 hematocri (A) 0.3210.02 0.3110.03 0.3210.03 hematocri (V) 0.3310.03 0.31+0.04 0.3110.04 pC02(V) 46.3813.42 61.86120.22 57.13115.83 hematocri {IJ) 0.3210.02 0.3210.04 0.3110.04
tp<0.05 at same time points
at 12 min. from start of fibrillation
Abbreviations: A-arterial sample from aorta, V-venous sample, IJ-internal jugular vein sample.
02 content in ml/dl (calculated as :p02 x 0.003) + (1.34 x
02 sat x hemoglobin) x 1/100 Table 3 . 02 Content (ml/dl )
Control DCLHb
Pig # 0 min 11 min 14 min Pig # 0 min 11 min 14 min
3 NT NT NT 2 13.61 14 .18 15. .80
6 12.47 12. ,83 13. .47 4 14.55 15 .95 14. .20
8 13.20 9. .59 11. .33 5 13.87 16, .25 16. ,34
11 NT NT NT 9 12.93 11 , .21 12. , 14
12 13.86 14. .99 15, .04 13 12.48 13, .00 NT
14 11.49 10. .30 9 .73 15 13.40 13, .40 NT
16 13.29 11. .71 10, .75 17 13.19 14 , .56 12. .97
20 12.48 11. .75 12. ,70 21 13.49 11 , .35 11. ,77 mean 12.80 11. 88 12. .17 mean 13.44 13. .74 13. .87
SD 0.83 1. .92 1. .94 SD 0.62 1 .88 1, .91
Cont rol DCLHb
Pig # 0 min 11 min 14 min Pig # 0 min 11 min 14 min
3 NT NT NT 2 12. .21 8.74 9.7
6 11. ,59 3. .04 NT 4 13. .77 6.24 5.64
8 11. ,3 NT NT 5 12, .83 11.37 10.74
11 NT NT NT 9 11. .44 3.91 4.58
12 11. ,8 7, .09 7. ,08 13 10. .94 8.8 7.97
14 4 .86 1, .22 1. .2 15 12. .05 5.84 3.72
16 8. .9 4. .78 5. ,08 17 11. ,75 7.84 7.4
20 11. 4 1. ,25 1. ,35 21 11. .41 3.16 3.12 mean 9. ,98 3. .48* 3. .68 mean 12. .05 6.99 6.61
SD 2. .72 2. .50 2. .89 SD 0 .90 2.73 2.79
Table 3. 02 Content (ml/dl) (cont'd)
Control IJ DCLHb
Pig # 0 min 11 min 14 min Pig # 0 min 11 min 14 min
3 NT NT NT 2 11.03 10.21 12. .36
6 9.14 5.60 4 14.06 3.98 5 .88
8 12.81 7.46 7, .42 5 13.78 10.82 10. ,59
11 NT NT NT 9 12.35 5.02 5. .83
12 11.67 9.30 8. .38 13 11.98 11.37 9. .45
14 6.83 4.05 3, .31 15 8.21 4.44 2. .61
16 12.43 6.89 5, .82 17 12.67 11.75 9. .96
20 11.68 1.31 1, .40 21 11.16 4.97 4. .46 mean 10.76 5.77 5. .27 mean 11.91 7.82 7. .64
SD 2.31 2.81 2. .89 SD 1.85 3.48 3, .41
*p<0.05 (two groups comparing at same time point)
NT: sample not taken (not able to calculate, see Table 2 for calculation)
Table 4. Mean Blood Pressures
Control Group
Parameter Baseline 11 Min. 14 Min.
(LV)S 115.9117.86 82.38+19.29V 74.25+25.94
(A)s 96.38112.42 62.88+13.62V 55.38+8.91
(PA)s 18.00+11.35 57.50+19.72V 54.00+22.48
(LV)d 2.6312.72 6.0016.05V 5.2514.83
(A)d 72.00114.24 15.25+7.17V 13.00+9.18
(PA)d 8.50+7.37 12.6715.47V 10.00+2.77
CoPP 69.38113.31 9.25+5.12V 7.7517.63
CePP 60.00110.002 6.33+6.62*V 3.40+9.37**
DCLHb Group
Parameter Baseline 11 Min. 14 Min.
(LV)ε 120.0117.5 79.75+23.48V 70.13125.35
(A)s 110.9116.08 78.14+18.08V 64.13120.19
(PA)s 17.4318.52 61.71126.23V 60.86125.35
(LV)d 3.6313.66 7.8813.14V 6.3813.38
(A)d 87.00+16.24 23.00+7.48V 21.25+8.10
(PA)d 8.0016.37 10.8615.18V 14.00110.25
CoPP 83.38114.74 14.4318.56V 14.5018.54
CePP 84.86116.27 19.29111.25V 21.2918.75
* p<0.05
**p<0.001 (group A vs. group B as same time pointε, two- sample t-test) V at 12 min. from start of fibrillation Abbreviations: A - arterial sample from aorta; V- venouε εample from pulmonary artery; (LV)s and (LV)d - left ventricular εystolic and diastolic blood pressure;
(A)s and (A)d - aortic systolic and diastolic blood presεure; (PA)ε and (PA)d - pulmonary artery systolic and diastolic blood presεure; CoPP - coronary perfuεion preεsure (calculated as aortic diastolic pressure - LV diastolic presεure) ; CePP - cerebral perfusion preεεure
(calculated aε aortic diaεtolic pressure - pulmonary artery diastolic pressure) .
Table 5 Total Cardiac Output (L/min)
Control
Pig # NSR CPR
3 3.989 0.553 13.86%
6 NO NO NO
8 2.966 0.363 12.24%
11 3.176 0.837 26.35%
12 2.471 0.342 13.84%
14 3.757 1.045 27.81%
16 2.646 0.648 24.49%
20 2.005 0.583 29.08%
Mean 3.001 0.624 21.10%
SD 0.705 0.251 7.43%
DCLHb
Pig # NSR CPR
4 4.452 0.412 9.25%
7 4.811 1.116 23.20%
9 3.832 0.312 8.14%
13 3.119 0.75 24.05%
15 2.478 0.304 12.27%
17 2.393 0.53 22.15%
19 3.381 0.48 14.20%
21 4.273 0.849 19.87%
Mean 3.592 0.594 16.64%
SD 0.902 0.287 6.44%
NSR: during normal sinus rhythm
CPR: during cardiopulmonary resuscitation
NO: flow not obtained Table 6 Myocardial Blood Flow (ml/organ/min)
Control
Pig # NSR CPR
3 108.9 1.7 1.56%
6 NO NO NO
8 81.3 3.8 4.67%
11 115.9 13.3 11.48%
12 116.1 1.4 1.21%
14 81.4 14.4 17.57%
16 101 7.6 7.52%
20 74.9 4.5 6.01%
Mean 97.07 6.66 7.15%
SD 17.60 5.30 5.79%
DCLHb
Pig # NSR CPR
4 134.6 3.1 2.30%
7 148.5 18.4 12.39%
9 99.6 1.6 1.61%
13 94.2 14.9 15.82%
15 53.3 1.3 2.44%
17 126.1 21.1 16.73%
19 140 14.1 10.07%
21 188.9 36.6 19.38%
Mean 123.15 13.89 19.38%
SD 40.82 12.04 7.17%
NSR: during normal εinuε rhythm
CPR: during cardiopulmonary reεuscitation
NO: flow not obtained Table 7 Cerebral Blood Flow (ml/organ/min)
Control
Pig # NSR CPR
3 34.3 17.6 51.31%
6 NO NO NO
8 18.4 6.3 34.24%
11 19.5 20.7 106.15%
12 20.7 16.3 78.74%
14 c -> 29.4 116.21%
16 25.5 15.1 59.22%
20 15.2 14.8 97.37%
Mean 22.70 17.17 77.61%
SD 6.30 6.96 30.57%
DCLHb
Pig # NSR CPR
4 34.7 11 31.70%
7 25.5 12.9 50.59%
9 26.7 8.4 31.46
13 27.5 26.1 94.91%
15 23.5 3.5 14.89%
17 34.6 25.7 74.28%
19 23.1 12.7 54.98%
21 36.2 12.5 34.53%
Mean 28.98 14.10 48.42%
SD 5.35 7.92 26.08%

Claims

CfrAJM-SWHAT IS CLAIMED IS:
1. Use in a pharmacological preparation of stroma- free hemoglobin for the purpose of resuscitating a mammal undergoing cardiac arrest.
2. Use in a pharmacological preparation of stroma- free hemoglobin for the purpose of returning spontaneous circulation after performing cardiac pulmonary resuscitation and defibrillation on a mammal undergoing cardiac arrest.
3. Use in a pharmacological preparation of stroma- free hemoglobin for the purpose of minimizing cerebral or coronary perfusion pressure deterioration in a mammal undergoing cardiac arrest.
4. Use in a pharmacological preparation of stroma- free hemoglobin for the purpose of increasing venous oxygen content in a mammal undergoing cardiac arrest.
5. Uεe according to claim 1, 2, 3, or 4 wherein the preparation contains a single dose of stroma-free hemoglobin in an amount of 50 to 2,500 mg/kg of body weight of the mammal.
6. Use according to claim 1, 2 3, 4 or 5 wherein the stroma-free hemoglobin is chemically modified.
7. Use according to claim 6 wherein the chemically-modified, stroma-free hemoglobin iε crosslinked, conjugated or polymerized.
8. Use according to claim 7 wherein the chemically-modified, stroma-free hemoglobin is diaspirin crosεlinked.
9. A method for reεuεcitation of a mammal undergoing cardiac arreεt compriεing adminiεtering εtroma-free hemoglobin during ventricular fibrillation during cardiac pulmonary resuscitation, and defibrillating to effect return of spontaneous circulation.
10. The method of claim 9 wherein said cardiac pulmonary resuεcitation includes mechanically compreεεing the thoracic wallε to alternatively contract and expand the blood volume contained in the heart, thereby simulating the pumping action of the heart.
11. The method of claim 9 or 10 wherein the stroma- free hemoglobin is administered in a dose ranging from 50 to 2,500 mg/kg of body weight.
12. The method of claim 9, 10 or 11 wherein the stroma-free hemoglobin is chemically modified.
13. The method of claim 12 wherein the chemically- modified, stroma-free hemoglobin is crosεlinked, conjugated or polymerized.
14. The method of claim 13 wherein the chemically- modified, εtroma-free hemoglobin is diaspirin crosslinked.
15. The method of claim 9, 10, 11, 12, 13 or 14 wherein sodium bicarbonate is coadministered with the hemoglobin to prevent the onset of acidosiε during cardiac pulmonary resuscitation.
16. The method of claim 15 wherein the sodium bicarbonate dose is from 0.01 to 1.0 meq/kg of body weight per minute.
17. The method of claim 9, 10, 11, 12, 13, 14, 15 or 16 wherein epinephrine, lidocaine or atropine iε coadminiεtered with the hemoglobin.
PCT/US1996/013512 1995-10-06 1996-08-20 Therapeutic administration of hemoglobin in cardiac arrest WO1997012627A1 (en)

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JP9514246A JPH11512738A (en) 1995-10-06 1996-08-20 Therapeutic administration of hemoglobin in cardiac arrest
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