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.     

Electric stimulation and insulin coma

Summary Observations with nonconvulsive stimulation during insulin coma have been presented. The method is useful in arousing patients from coma, provided that they have not entered a deep phase. Adrenalin and blood sugar responses suggest that activation of the diencephalic pituitary-adrenal axis occurs. The theory that during insulin coma a successive inactivation of phylogenetic layers within the brain takes place is supported by the observations reported here. Therapeutic results suggest a favorable comparison with deep insulin coma, provided a differential and dynamic approach is followed. Complications, such as delayed and protracted coma, have not been encountered. Treatment time is shortened to about two hours, and the average number of treatments is about 40.Read at the 109th annual meeting of the American Psychiatric Association at Los Angeles, May 1953.     

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.     

Comparison of the effects of 4 psychiatric treatments on rat brain beta 5HT2 receptors]

Four psychiatric treatments, such as electro-convulsive treatment (ECT), insulin coma, electroacupuncture (EA) and antidepressants were given to rats chronically, and the brain cortex beta and serotonin2 receptors were measured. Comparing with their control groups we found that chronic ECT, insulin coma and EA have similar effect to down-regulate the specific coma and EA have receptor, but almost no effect on serotonin2 receptor. Antidepressants have various effects on brain monoamine receptors. The major effects of desipramine and imipramine were down-regulate B receptor, while of amitriptyline was down-regulate 5HT2 receptor. Our data suggested that different psychiatric treatment might effort their therapeutic effects mediated by different monoamine function in CNS.     

颅脑损伤合并非酮性高血糖高渗性昏迷

目的 探讨颅脑损伤并发非酮性高血糖高渗性昏迷病人的诊断、治疗及预后。方法 对1997年7月～2002年1月期间收治的17例中、重型颅脑损伤合并非酮性高血糖高渗性昏迷的病人进行回顾性分析。结果 17例颅脑损伤合并非酮性高血糖高渗性昏迷的病人，除1例之外，其余均在静滴胰岛素及胃内注水治疗后2d内，高血糖、高血渗得到控制。17例非酮性高血糖高渗性昏迷病例占同期中、重型颅脑损伤病人的1．76％。死亡3例，死亡率17．6％。结论 对非酮性高血糖高渗性昏迷，静滴胰岛素极其有效，救治的关键是及早发现行采取有效的治疗措施。治疗中连续性监测血糖、血清渗透压、电解质、严密的病情监护，及时有效调整胰岛素用量至关重要。     

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.     

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.     

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.     

Insulin-induced factitious hypoglycemic coma

Hypoglycemia due to the ingestion of oral hypoglycemic agents or injection of insulin is a common way for chronic factitious disorder to present to physicians. Despite this fact, factitious hypoglycemic coma is rare. Because hypoglycemia is potentially fatal, with numerous sequelae, physicians need to be aware of its occurrence and method of detection. A case of chronic factitious disorder presenting as hypoglycemic coma is presented and its implications discussed.     

Insulin coma therapy: Decrease of plasma tryptophan in man

Summary A biochemical study was performed in two patients submitted to insulin coma therapy. The injection of insulin resulted in a decrease of free and total tryptophan as well as tyrosine in plasma, while NEFA were not influenced by this treatment. The ratio of tryptophan to tyrosine was enhanced. The administration of glucose after insulin provoked an increase of free and total tryptophan. The results support the hypothesis that in man insulin may favor the uptake of tryptophan by the brain, and enhance the synthesis of cerebral serotonin.     

Insulin-induced hypoglycemic coma and regional cerebral energy metabolism

Swiss-Albino female mice weighing 20 g were rendered hypoglycemic by injecting insulin (2 units/kg). Animals were sacrificed at 40 min (pre-coma), 2 h (coma) and 4.5 h (recovery) after insulin injection by rapid submersion in liquid N₂. Following sectioning at 20 μm, samples from the ascending reticular activating system and the inferior colliculus were freeze-dried and assayed for glucose, lactate, ATP and phosphocreatine (PCr).There was a preferential effect of hypoglycemia on ATP and PCr in cells of the ascending reticular activating system. ATP was depleted 30%, and PCr 55% in the pre-coma stage. ATP and PCr in cells from the inferior colliculus were not decreased. This selective effect on cells of the ascending reticular activating system followed by coma suggests that the coma per se may not represent total failure of the organism, but rather a compensatory mechanism designed to permit the animal to correct its compromised energy status.     

血糖与脑卒中意识障碍及近期预后的关系

本研究纳入146例急性脑卒中患者,测定其发病早期血糖值,同时对其意识状况进行GCS评分,并观察其近期预后。结果提示早期血糖水平与GCS呈明显负相关关系,高血糖组昏迷发生率和病死率均明显高于非高血糖组,近期预后差,昏迷组及死亡组血糖均值和高血糖发生率均明显高于非昏迷组及存活组。治疗上推荐使用胰岛素,而且应尽量避免引起血糖增高的因素,使血糖维持在正常水平,以期能改善息者的近期预后和减少神经功能缺损。     

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.     

Prolonged coma in the insulin treatment of dementia praecox

Conclusion We believe that in cases of prolonged insulin coma the clinical signs observed are explained on the basis of actual cellular pathology. We consider the process to be an encephalopathy caused by interference with normal oxidative processes.     

Diabetes mellitus in Kearns-Sayre syndrome

A 20-year-old woman with Kearns-Sayre syndrome (KSS) suddenly experienced two episodes of diabetic coma. She was studied to determine whether diabetes mellitus (DM) resulted from insulin resistance or from an insulin secretion abnormality, using the euglycemic glucose clamp technique and the glucagon tolerance test. She had a deficiency of insulin secretion from beta cells. It is important to recognize in practice the onset of DM in patients with mitochondrial myopathy. We would suggest that a genetic linkage or mitochondrial dysfunction may be responsible for the association of both disease states.     

Modulation of dopamine receptor supersensitivity by chronic insulin: implication in schizophrenia

Haloperidol-induced increases in the number of dopamine receptors, as measured by [³H]spiperone binding to striatal membranes, do not occur in rats repeatedly treated with insulin in doses eliciting pronounced hypoglycemia. Given alone, however, insulin has no effect on [³H]spiperone binding in normal rats. These findings demonstrate a modulating effect of insulin on brain dopamine receptor sensitization. This effect might be relevant to the mechanism of insulin coma therapy in schizophrenia and is consistent with and supports the dopaminergic hypothesis of this disorder.     

Cerebral mitochondrial respiration in diabetic and chronically hypoglycemic rats

The respiratory function of cerebral mitochondria harvested from genetically diabetic (BB/W) and streptozotocin-diabetic rats deprived of insulin for 3-4 weeks was found to be unchanged from control values. Furthermore, insulin-deprived BB/W rats subjected to 30 min of insulin-induced hypoglycemic coma demonstrated a normal mitochondrial respiration following a 60 min period of glucose restitution, a finding consistent with earlier results in non-diabetic rats. However, in rats exposed to 1 week of moderate hypoglycemia (plasma glucose = 3.0 mumol.ml-1), both state 3 respiration and the respiratory control ratio (RCR) were reduced from control. In fact, when the chronic hypoglycemia was imposed following a 3-4 week period of diabetic hyperglycemia, the state 3 rate and RCR were found to be reduced to a greater degree than in chronically hypoglycemic, non-diabetic, previously normoglycemic rats. Finally, when 1 week of moderate hypoglycemia preceded a 30 min period of insulin-induced hypoglycemic coma, a disturbed pattern of mitochondrial respiration (i.e. increased state 4, decreased RCR) was found at 60 min of recovery following coma. These results indicate that chronic increases in glucose (and insulin deprivation) have no effect on cerebral mitochondrial respiratory function, whereas prolonged, albeit moderate, reductions in cerebral glucose supply result in perturbations in mitochondrial respiration. These results demonstrate the importance of an adequate glucose supply for normal mitochondrial activity.     

Multi‐modal brain imaging showing brain damage to the orbitofrontal cortex and left hemisphere,in a case of prolonged hypoglycemia‐induced transient hemiplegia followed by persistent encephalopathy

A 21‐year‐old left‐handed male patient was admitted with a 19‐h history of coma after substantial insulin injection for suicide attempt. Although the patient recovered from coma 3 days after injury, he experienced transient hemiplegia followed by permanent brain damage. Electroencephalogram (EEG), brain magnetic resonance imaging (MRI), and brain single‐photon emission computed tomography (SPECT) identified the localization of this dysfunction, but consistency between clinical symptoms and brain images changed depending on the course of treatment. Transient hemiplegia corresponded to abnormal waveforms on EEG and decreased cerebral blood flow on SPECT, whereas persistent dysfunctions corresponded to abnormal brain regions on MRI and SPECT.     

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.     

Effects of insulin-induced hypoglycemia on intracellular pH and impedance in the cerebral cortex of the rat

In order to evaluate changes in extra- and intracellular pH in the brain during hypoglycemia rats were injected with insulin and pH changes evaluated when the EEG showed a slow-wave-polyspike pattern (‘precoma’), or when EEG activity had ceased for 5, 15 or 30 min (‘coma’). Extra- and intracellular acid-base changes were evaluated from pCO₂ and HCO₃-concentrations. In order to allow calculation of intracellular pH (and HCO₃-concentrations) changes in extracellular fluid volume were estimated by measurements of cortical tissue impedance. The main results were as follows.

1. (1) At constant arterial pCO₂ the CSF HCO₃-concentration either rose (15 min of coma) or remained unchanged (all other groups). However, since the cerebrovenous (and tissue) pCO₂ fell, all groups except one (30 min of coma) showed a significant increase in extracellular fluid pH.

2. (2) During severe hypoglycemia, and especially when EEG activity ceased, cortical impedance increased markedly. Calculations with the help of the Rayleigh and Maxwell equations showed that the extracellular fluid volume was reduced to about 50% of control.

3. (3) Intracellular pH increased significantly in precoma and in coma of 15 and 30 min duration. However, pH in the 5 min coma group was significantly lower (but no different from control).

4. (4) In general, the increase in intracellular pH is consistent with previous findings that hypoglycemia is associated with oxidation of endogenous acid metabolites. However, the data suggest that in the initial period of coma acids accumulate by some unidentified mechanism.