The use of hyaluronidase with insulin in insulin coma therapy

Summary A study of the use of hyaluronidase in conjunction with insulin, in deep coma insulin therapy, has been described. Fifty-one patients participated in this project—24 men and 27 women. Six patients were refractory to insulin; 12 were started on insulin coma therapy at the beginning of the study. Fifty-one received the mixture of insulin plus hyaluronidase for one month, during different phases of their treatment. A total of 2,968 injections of insulin were given. The property of hyaluronidase to reduce the number of spontaneous convulsions during insulin coma therapy, is pointed out. Alidase, a brand of hyaluronidase, was used in this project.     

A new aid to insulin coma therapy

Summary A new method of controlling insulin coma has been developed. It lessens some of the difficulties which have complicated deep insulin coma therapy.     

Delayed-onset encephalopathy and coma in acute organophosphate poisoning in humans

The objective of the study was to describe the clinical characteristics and course of delayed-onset organophosphate (OP) poisoning. In our clinical experience, we have noticed patients with onset of deep coma 4-7 days after hospital admission, clinical features that have not been previously described. We set up a prospective observational study over 1 year to formally characterize this observation. Thirty-five patients admitted to the intensive care unit (ICU) with severe OP poisoning and treated with atropine and supportive therapy were followed up. Oximes were not administered. Three patients developed delayed-onset coma after presenting with normal or near normal Glasgow coma score (GCS). They developed altered conscious state rapidly progressing to deep coma, 5.0+/-1.0 (mean+/-S.D.) days after OP ingestion. The GCS persisted at 2T for 4.3+/-2.1 days despite the cessation of sedative drugs at the onset of coma. During this period, the patients had miosed non-reacting pupils and no clinically detectable cortical or brainstem activity. Computed tomography of the brain and cerebrospinal fluid analysis were normal. Electroencephalogram showed bihemispheric slow wave disturbances. Two patients required atropine during this period to maintain heart rate and reduce secretions. In all three patients, no metabolic, infective or non-infective cause of altered conscious state was identified. With supportive therapy the GCS improved to 10T in 8.0+/-2.0 days. All patients survived to hospital discharge. Three other patients who developed a reduction in GCS (3T-7T) by 4.7+/-1.2 days but not progressing to coma and recovering (GCS 10T) in 3.3+/-0.6 days may have manifested delayed-onset encephalopathy. Delayed-onset coma appears to have a distinct clinical profile and course with complete resolution of symptoms with supportive therapy. Although persistent cholinesterase inhibition is likely to have contributed to the manifestations, the mechanism of coma and encephalopathy need to be explored in further trials. The good outcomes in these patients suggest that therapy should not be limited in OP-poisoned patients developing profound coma or encephalopathy during hospitalization.     

An investigation of the role played by oxygen and by cellular respiration in hypoglycemic coma

Summary It has been found that when oxygen is given to patients during insulin coma, the coma is intensified. It is suggested that, in hypoglycemia, the oxygen, that normally would combine with glucose, accumulates in the blood instead, increasing the pH and thereby inactivating the enzymes responsible for cellular respiration. Obviously if these views are correct, oxygen in excess must be regarded as a toxic substance and should never be administered in insulin coma emergencies. On the other hand, methylene blue, a substitute for the non-functioning enzymes, has been found to reestablish the normal processes quickly and safely when used in conjunction with the usual dextrose solution.Read at the Up-state Interhospital Conference of the New York State Department of Mnetal Hygiene at Syracuse Psychopathic Hospital, April 9, 1956.     

SECRETION OF HUMAN GROWTH HORMONE DURING INSULIN COMA AND ELECTROSHOCK THERAPIES

The responses of plasma HGH during psychiatric shock therapies were investigated, and the mechanisms of HGH secretion and of shock therapies were discussed. 1. The response following a sinall dose of i.v. insulin administrotion. a) The plasma HGH following 0.1 U/kg of i.v. insulin in schizophrenic patients showed marked elevation in six out of seven cases. It reached to the peak value of 30.4±9.2 mμg/ml between 60 and 90 minutes after i.v. insulin. b) This type of response was not affected by the various psychotropic drugs that were administered orally in controlling the mental symptoms of the patients. c) Intramuscular injection of chlorpromazine (30–50 mg) did not alter the pattern of the plasma HGH response. 2. Insulin coma therapy a) A marked elevation of plasma HGH level was observed in all cases of schizophrenia during insulin coma therapy. The peak value was 9–32 mμg/ml (average 22.6±8.1 mμg/ml). b) A tendency of delay in reaching the peak value was observed in the determination performed in the second week of coma days as compared to the initial determination in the early days of insulin coma. A tendency was observed that better therapeutic results were correlated with the absence of or decrease in the delay in reaching the peak value in the course of insulin coma therapy. c) The protracted insulin coma was associated with the marked decrease in the magnitude of the peak value of plasma HGH as compared to the initial determination, suggesting the presence of a fatigued state of the central mechanism regulating the secretion of HGH. 3. Electroshock therapy a) Elevation of the plasma HGH level was observed after electroshock therapy in five of six cases of schizophrenia. A non-responsive case was found to be moderately obese. A case of depression and a case of atypical psychosis lacked HGH response after EST in the absence of obesity. b) The peak value after the electroshock therapy was lower than the one during insulin coma therapy or after administration of a small dose of i.v. insulin. The average peak value after EST was 8.1±6.8 mμg/ml. c) The responsivity of plasma HGH was found to be unrelated to the various prernedications, such as i.v. thiopental and succinylcholine chloride. It was also concluded that the presence or absence of generalized convulsion was not related to the responses of HGH following EST. d) No correlation was found between the changes of blood sugar level and the type of plasma HGH responses following the EST. It was suggested that the elevation of HGH at the time of electroshock therapy was induced by the direct electric stimulation of the hypothalamic center, but the effect of stimulating the HGH secretion was much lower than that induced by the insulin coma or i.v. insulin administration.     

Brain metabolism after recurrent insulin induced hypoglycaemic episodes: a PET study.

Neuropsychological testing was carried out and the rate of oxygen metabolism in the brain was measured by PET in 15 highly selected patients with type 1 diabetes. The aim was to investigate the impact on the brain of hypoglycaemic comas resulting from insulin treatment. No significant difference was found between nine patients with a history of more than 10 hypoglycaemic comas and six others who denied any history of such events. These data suggest that intensified insulin treatment, although increasing the frequency of hypoglycaemic coma, may not always be harmful for the brain. This may be explained by the limited duration of hypoglycaemic coma induced by conventional insulin treatment.     

Heart rate variability in brain death

The sensitivity and specificity of heart rate variability (HRV) in the corroboration of brain death diagnosis in patients with acute traumatic intracranial lesions was evaluated in 20 patients with clinical criteria of brain death, nine patients in deep coma (Glasgow scale <7) and 18 normal controls, all age matched. The electrocardiogram was sampled at 650 Hz and several parameters of HRV were calculated, in both time and frequency domains. The HRV parameters were significantly lower in the brain death group compared with the deep coma group. Linear discriminant analysis between brain death and deep coma patients was performed on a data set made of nine randomly selected patients with clinical criteria of brain death and nine patients in deep coma. Cross-validation was performed on the remaining 11 patients with clinical criteria of brain death. All patients in the data set were correctly classified (sensitivity and specificity of 100%). All patients in the cross-validation set were correctly classified (sensitivity of 100%). Further studies are necessary to evaluate the specificity of the method in the independent set of deep coma patients and in the follow-up of comatose and vegetative patients to identify irreversibility of HRV. Nevertheless, these results suggest that HRV analysis constitutes a fully sensitive and specific method for assessing brain death in potential organ donors with acute traumatic lesions of the brain. This fast, quantitative and bedside method seems very promising for the early confirmation of brain death, which is an important factor for the success of transplantation procedures and could have a high predictive value of brain death in comatose patients with brain injuries without fully diagnostic criteria.     

Which EEG patterns in coma are nonconvulsive status epilepticus?

Nonconvulsive status epilepticus (NCSE) is common in patients with coma with a prevalence between 5% and 48%. Patients in deep coma may exhibit epileptiform EEG patterns, such as generalized periodic spikes, and there is an ongoing debate about the relationship of these patterns and NCSE. The purposes of this review are (i) to discuss the various EEG patterns found in coma, its fluctuations, and transitions and (ii) to propose modified criteria for NCSE in coma.Classical coma patterns such as diffuse polymorphic delta activity, spindle coma, alpha/theta coma, low output voltage, or burst suppression do not reflect NCSE. Any ictal patterns with a typical spatiotemporal evolution or epileptiform discharges faster than 2.5 Hz in a comatose patient reflect nonconvulsive seizures or NCSE and should be treated. Generalized periodic diacharges or lateralized periodic discharges (GPDs/LPDs) with a frequency of less than 2.5 Hz or rhythmic discharges (RDs) faster than 0.5 Hz are the borderland of NCSE in coma. In these cases, at least one of the additional criteria is needed to diagnose NCSE (a) subtle clinical ictal phenomena, (b) typical spatiotemporal evolution, or (c) response to antiepileptic drug treatment. There is currently no consensus about how long these patterns must be present to qualify for NCSE, and the distinction from nonconvulsive seizures in patients with critical illness or in comatose patients seems arbitrary.The Salzburg Consensus Criteria for NCSE [1] have been modified according to the Standardized Terminology of the American Clinical Neurophysiology Society [2] and validated in three different cohorts, with a sensitivity of 97.2%, a specificity of 95.9%, and a diagnostic accuracy of 96.3% in patients with clinical signs of NCSE. Their diagnostic utility in different cohorts with patients in deep coma has to be studied in the future.This article is part of a Special Issue entitled “Status Epilepticus”.     

Re-evaluation of short latency somatosensory evoked potentials (P13, P14 and N18) for brainstem function in children who once suffered from deep coma

One of the major clinical features of brain death is deep coma. Therefore, we re-evaluated retrospectively electrophysiological examinations of brainstem function in about 31 children who had once suffered from deep coma in order to reveal its pathophysiological characteristics. The patient age at coma ranged from 1 month to 10 years (mean 2 years 1 month). The electrophysiological examinations were performed, including any of short-latency somatosensory evoked potential (SSEP), brainstem auditory evoked potential (BAEP) and blink reflexes. We first compared results between the fair and poor prognostic groups, and then re-evaluated SSEP results on a few severely impaired patients with persistent vegetative state (PVS). Subsequently, SSEP clarified more specific findings for a deep coma condition than BAEP and blink reflex. A lack of P14, N18 and N20, and an amplitude reduction or vagueness of P13 in SSEP in these children strongly suggested high risk in their future neurological prognosis. In conclusion, electrophysiological examinations, especially SSEP (P13, P14 and N18), might be very useful in obtaining a long-term neurological prognosis after deep coma in children.     

Blink reflexes in severe traumatic coma.

Blink reflexes were studied in 21 patients in coma after severe head injury. Our observations suggest that blink reflexes are a simple, objective, neurophysiological test to evaluate brainstem function. Correlations between these reflexes and the anatomoclinical stanges of coma and the Glasgow coma scale have been established. Presence of the early R1 component shows the integrity of at least a part of the pontine structures. The appearance of the late R2 component is correlated with a better chance of recovery from coma.     

Lessons from the insulin story in psychiatry

For nearly 20 years, from the mid-1930s until the mid-1950s, early cases of schizophrenia were treated, and surprisingly successfully treated, by deep insulin coma therapy. This paper is an attempt to explore what, if any, lessons there are to be gained for us 30 years later from a treatment regime that turned out to have nothing to do with insulin per se. Such lessons as there may be from our recent historical past may help us to foster our critical acumen and commonsense as we try in our daily practice to understand how we can best help our patients in safety.     

最小意识状态的定义、诊断标准及临床鉴别

最小意识状态可由急性脑损伤后昏迷或植物状态、变性或先天性神经系统疾病发展而来，有严重意识障碍，但病人既不符合昏迷也不符合植物状态的诊断，存存部分意识鉴别最小意识状态、昏迷及植物状态对于预后的判定有重要的意义。本文主要综述最小意识状念的定义、诊断标准、鉴别诊断及有关临床意义。     

Recurrent coma and Lesch-Nyhan syndrome.

A patient with Lesch-Nyhan syndrome has had 3 recurrent episodes of coma, each associated with an acute illness. Extensive investigation for known causes of coma has failed to yield a diagnosis. Although coma is not generally recognized as a feature of Lesch-Nyhan syndrome, similar patients have been reported previously. This and other episodic phenomena observed in Lesch-Nyhan syndrome may be explained by the disruption of cellular energy metabolism due to purine depletion, consequent to lack of the purine salvage pathway normally provided by the hypoxanthine-guanine-phosphoribosyl-transferase enzyme.     

Extracellular pH in the rat brain during hypoglycemic coma and recovery

It has previously been shown that hypoglycemic coma is accompanied by marked energy failure and by loss of cellular ionic homeostasis. The general proposal is that shortage of carbohydrate substrate prevents lactic acid formation and thereby acidosis during hypoglycemic coma. The objective of the present study was to explore whether rapid downhill ion fluxes, known to occur during coma, are accompanied by changes in extra- and/or intracellular pH (pHe and/or pHi), and how these relate to the de- and repolarization of cellular membranes. Cortical pHe was recorded by microelectrodes in insulin-injected rats subjected to 30 min of hypoglycemic coma, with cellular membrane depolarization. Some rats were allowed up to 180 min of recovery after glucose infusion and membrane repolarization. Arterial blood gases and physiological parameters were monitored to maintain normotension, normoxia, normocapnia, and normal plasma pH. Following depolarization during hypoglycemia, a prompt, rapidly reversible alkaline pHe shift of about 0.1 units was observed in 37/43 rats. Immediately thereafter, all rats showed an acid pH shift of about 0.2 units. This shift developed during the first minute, and pHe remained at that level until repolarization was induced. Following repolarization, there was an additional, rapid, further lowering of pHe by about 0.05 units, followed by a more prolonged decrease in pHe that was maximal at 90 min of recovery (delta pHe of approximately -0.4 units). The pHe then slowly normalized but was still decreased (-0.18 pH units) after 180 min when the experiment was terminated. The calculated pHi showed no major alterations during hypoglycemic coma or after membrane repolarization following glucose administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Physiologic and prognostic significance of "alpha coma".

A patient with posthypoxic "alpha coma" is described whose EEGs were recorded before coma, within two hours following the onset of coma and after recovery. The differences observed between the alpha activity during coma and that seen before and after suggest that the alpha activity during coma and the physiologic alpha rhythm are different phenomena. This case, as well as others reported, also suggests that "alpha coma" resolving in the first 24 hours following hypoxia may have a better prognosis than "alpha coma" detected after the first day, and stresses the need for EEG monitoring begun in the immediate period following hypoxia in order to assess accurately the prognostic significance of this EEG pattern in the early stages of postanoxic encephalopathy. The aetiology of "alpha coma" also affects outcome. The survival rate appears higher in patients with respiratory arrest than in those with combined cardiopulmonary arrest.     

Transient organic mental reactions during shock therapy of the psychoses: A clinical study

Summary Recapitulating the above cases, we find that in Case 1, after two months of therapy, protracted coma followed an insulin dosage of 160 units. Previous similar dosage, with identical duration of coma, did not result in a protracted reaction following gavage. The patient had been maintained on a similar or even smaller daily insulin dosage for a considerable time prior to the protracted coma. There was consistent conformity of the electroencephalographic and psychological performances with the clinical status, all three exhibiting simultaneous improvement.In Case 2, following the fifteenth convulsive seizure, induced by 9 1/2 c.c. of metrazol, a clinically organic reaction (confusion, memory defect and disorientation) was correlated with an abnormal electroencephalogram, which became normal as the patient's clinical status returned to normal.Case 3 demonstrated the same correlation.Cases 4 and 5 revealed abnormal brain waves associated with severe memory defect.From the department of psychiatry, New York State Psychiatric Institute and Hospital. Read at the interhospital conference held at the Utica State Hospital, Utica, N. Y., April 26, 1940.     

The use of glucagon in insulin coma therapy

Summary The use of glucagon in the termination of insulin coma therapy has been discussed. The advantages over previous techniques of termination were described. Clinical experience with 41 patients who had a total of 739 comas showed no untoward reactions with the use of glucagon. No permanent residual effects were noted, and only transitory reactions, such as delayed coma, muscular twitching and secondary comas were reported in six instances.It has been demonstrated that glucagon is an effective, reliable and safe drug in the termination of insulin coma therapy. Its introduction as a therapeutic agent has demonstrated once more the many benefits which can be derived from basic medical research.From the department of neurology and psychiatry, Chicago Wesley Memorial Hospital and from the department of neurology and psychiatry, Northwestern University Medical School, Chicago, Ill.     

Electroencephalographic assessment of coma.

SUMMARY: Altered mental status ranging from confusion to deep unresponsiveness can be described as coma. Electroencephalography is an important tool in assessing comatose patients. Some EEG patterns are seen with lighter stages of coma and have a good prognosis, whereas others are seen in deep, often irreversible coma. These EEG patterns carry a much more grave prognosis. This paper discusses the various EEG features seen in coma, ranging from intermittent rhythmic delta activity to electrocerebral inactivity. A discussion regarding etiology and prognosis is presented after the EEG pattern is described in detail. Special EEG features, such as alpha coma, beta coma, spindle coma, etc., are discussed toward the end.