Case Report

Noncardiogenic acute pulmonary edema due to severe hypoglycemia-an old but ignored cause^B

Abstract

We present a rare case of Noncardiogenic pulmonary edema (NCPE) associated with sudden coma due to severe hypoglycemia. We suggest that in every case of NCPE associated with coma, a rapid determination of glycemia should be provided because Delays in diagnosis can lead to adverse outcome.

Noncardiogenic acute pulmonary edema (NCPE) can have a wide range of differential causes, including sepsis, severe trauma, narcotic overdose, pulmonary embolism, and virtually, any moderate or severe acute neurological injury [1,2]. Severe hypoglycemia can lead to severe neurological dysfunction and even death. However, medical textbooks do not currently include hypoglycemia among the possible causes of NCPE [1]. However, this association was well known several decades ago, when insulin used to be prescribed for the treatment of schizophrenia but became currently forgotten [3,4]. To the best of our knowledge, this is the first case reported in the last 30 years in an emergency medical journal.

A 49-year-old man was admitted to the hospital because of sudden coma (Glasgow Coma Scale [GCS] = 4) and brisk pulmonary edema.

The patient had a history of alcohol abuse. Medical history was unknown.

Nine hours before admittance, the patient was brought to the emergency department (ED) with minor traumatic head injury secondary to falling, shortly after a heavy drink. He presented tonic seizures at an unknown time before admission but otherwise he did not loose consciousness. On admission, he appeared lean, drowsy, and slightly disoriented. Glasgow Coma Scale score was 14 (eyes = 4 [E4], verbal = 4 [V4], motor = 6 [M6]). Neurological examination showed no focal signs and no neck stiffness. The pupils were normal, equal, and reactive to light. Eye movements and tendon reflexes were normal.

^? Support: Grant number 242/2007 of the Romanian Ministry of Education and Research, National Programme II (PNII) for the study of acute heart failure.

Mild signs of dehydration were present, with mild hypotension (85/60 mm Hg). The result of the rest of cardiovascular examination was normal. The lungs were clear. The abdomen was rigid but not tender, without any organomegaly.

On presentation to the ED, blood glucose level was 388 mg/dL, without signs of diabetic hyperosmosis or ketoaci- dosis. There was mild increase in creatinine, creatine kinase levels, and white blood cell count, attributed to dehydration and trauma. Cerebrospinal fluid tests showed a protein level of 30 mg/dL (reference range: 12-60 mg/dL), no white cells, but with 144 red cells/mm³ (reference range: none). The rest of relevant tests are shown in Table 1. The lung fields were clear, and heart size was normal on chest x-ray examination (Fig. 1).

The patient received 12 U of rapid acting insulin subcutaneously, 1000 mL of Ringer lactate, and 500 mL of 0.9% sodium chloride solution intravenously. Blood pressure normalized, and the patient remained stable for the following hours.

Nine hours after presentation, patient developed sudden coma and severe pulmonary edema. The GCS score was 4 (E1, V1, M2), with pinpoint, unreactive to light, and no spontaneous breathing. cardiac auscultation revealed no murmurs or S3 sound. Heart rate was 62 beats per minute (bpm). Blood pressure dropped to 60/30 mm Hg. Patient was intubated, and abundant spotty secretions were aspirated. ventilatory support was provided. Although dopamine 10 ug kg-1 min-1 was initiated, there was persistent hypotension and progressive Sinus bradycardia to a minimum heart rate of 34 bpm during the next hour.

Initial electrocardiogram (ECG) showed sinus rhythm, normal QRS complexes, and long QTc interval with non- specific wave changes. Fifteen minutes afterward, T waves became deeply inverted in the precordial leads (Fig. 2, left).

Precordial echocardiography showed no structural heart disease, with preserved left ventricular ejection fraction (50%), trace Mitral regurgitation, nondilated left atrium, and age-related diastolic dysfunction, with no signs of increased diastolic left ventricular pressures (estimated by E/E? = 7, where E is the pulsed Doppler wave velocity of early diastolic filling at the tip of the mitral valve and E? is the early diastolic septal mitral annular velocity) [5].

A provisional diagnosis of Neurogenic pulmonary edema, due to either subarachnoid hemorrhage or pontine

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Table 1 Relevant	blood tests during admission
		Admission	20 h	40 h	5th day	Reference range
Biochemistry	Glucose (mg/dL)	388	97	-	76	70-115
	Urea (mg/dL)	66	64	-	21	10-40
	Creatinine (mg/dL)	1.4	0.9	-	0.7	0.6-1.2
	Sodium (mmol/L)	139	130	138	144	132-147
	Potassium (mmol/L)	3.5	2.9	3.4	4.1	3.5-5.1
	CKMB (U/L)	17	-	7	-	1-25
	CK (U/L)	230	-	173	-	30-150
	ALT (U/L)	38	29	-	-	10-37
	AST (U/L)	44	68	-	-	10-37
	Total bilirubin (mg/dL)	0.7	-	-	-	0.2-1.3
	Amylase (U/L)	87	-	-	-	30-110
	PT (s)	12.3	11.2	-	-	11-13.2
	aPTT (s)	32.7	26.5	-	-	22-38
Hematology	White cell count (per mm3)	11 700	9200	-	-	4000-9000
	Neutrophils (per mm3)	10 100	8600	-	-	3000-7000
	Hemoglobin (g/dL)	13	12.1	-	-	11-15.5
	Mean corpuscular volume (fl)	99.5	98.6	-	-	85-96
	Platelets (x103/mm3)	619	480	-	-	150-350
CKMB indicates Creatine phosphokinase MB fraction; CK, total creatine phosphokinase; ALT, alanine transaminase; AST, aspartate transaminase; PT, prothrombin time; aPTT, activated partial thromboplastin time.

stroke, was made. The computed tomographic (CT) scan showed a 6-mm-thick old right subdural parietal hematoma (Fig. 2, right, arrow) and small prepontine pneumocephalus (Fig. 2, right, arrowheads) without mass effect.

Repeated glycemia 1 hour after the onset of coma was 19 mg/dL. Immediate intravenous glucose was administered. The neurological status rapidly improved. Two hours later, glycemia was 125 mg/dL, and the patient was conscious, agitated, and without focal neurological signs. The pupils were normal and reactive to light. Lung fields were clear. Heart rate and blood pressure returned to normal. Patient was extubated and dopamine was stopped. Negative T waves on ECG persisted for longer than 24 hours but disappeared by the seventh day, with only flat T wave persisting in the precordial leads (Fig. 2, left). The patient was discharged after 7 days without neurological dysfunction.

We presented a rare case of hypoglycemia-induced NCPE in an alcoholic man, due to iatrogenic overdosage of insulin. In this case, Echocardiographic examination essentially ruled out cardiogenic pulmonary edema. Initial diagnosis of neurogenic pulmonary edema was supported by the triad of sudden coma with signs of pontine dysfunction, brisk pulmonary edema, and the ECG changes described previously (Fig. 2, left). Those findings, together with red cells on cerebrospinal fluid tests, suggested a diagnosis of SAH [6]. However, the CT scan did not reveal intracranial lesions compatible with neurogenic pulmonary edema. Both old subdural hematoma and pneumocephalus did not produce any mass effect (Fig. 1, right). Those CT findings are frequent in alcoholic men with a history of head trauma [2]. Our patient presented with Mild head trauma (GCS 14), which is not described as a cause of

NCPE [7].

Subarachnoid hemorrhage can be missed at CT examina- tion if the amount of blood is small; however, mild SAH cannot be a cause of NCPE [6]. Thus, the presence of red cells in the cerebrospinal fluid in our patient was probably related to the lumbar puncture.

The CT examination cannot rule out pontine stroke as a cause of NCPE, but the fact that all the features were rapidly reversed once hypoglycemia was treated strongly supports the causal relationship between severe hypoglycemia and NCPE in this patient.

The proposed mechanism for hypoglycemia-induced NCPE is neurogenic [8-11]. Previous reports [3,8,11]

Fig. 1 Posteroanterior chest x-ray at admission. Lung fields are clear, with no pulmonary congestion. Heart size is normal.

Fig. 2 Left: ECG changes during admission. Deep negative T waves in precordial leads appeared 15 minutes after the onset of pulmonary edema and persisted longer that 24 hours. Corrected QTc interval was 480 milliseconds during pulmonary edema but normalized in the following ECGs. Right: CT of the head (transverse view, upper panel, and sagittal reconstruction, lower panel) shows small parietal subdural hematoma (arrows) and small pneumocephalus without mass effect (arrowheads).

described a clinical hyperadrenergic status during hypo- glycemia-induced NCPE, manifested by tachycardia, hypertension, and dilated pupils. Contrary to these reports, our patient developed progressive bradycardia and pinpoint pupils. These features suggest severe associated pontine dysfunction. Our patient also developed profound hypoten- sion unresponsive to dopamine which suggests associated neurogenic shock [12].

Seizures are frequently associated with subsequent NCPE during severe hypoglycemia [9]. In this case, we considered the seizures in the context of alcohol abuse and minor Traumatic head injury [2] because hyperglycemia was documented at presentation.

electrocardiogram abnormalities in severe hypoglycemia include long QTc interval [13] and deeply inverted nonischemic T waves in anterior precordial leads [14]. These are very similar to the ones described in SAH and pontine stroke, where NCPE is frequent [6]. These changes were also present in our case.

In this case, determining the glucose level at the time of onset of neurogenic complications would have prevented unnecessary investigations. Another important issue raised by this case is the danger of insulin treatment when hyperglycemia is not a medical emergency.

Physicians in the EDs can encounter rare causes of pulmonary edema which are not included in the differential causes described in current medical textbooks, such as hypoglycemia. In these cases, delays in diagnosis can potentially lead to severe outcome. We suggest that in each case of pulmonary edema associated with coma, a rapid determination of glycemia should be provided. Meanwhile,

insulin treatment should be postponed if hyperglycemia is not considered a medical emergency.

Andrei D. Margulescu MD Roxana C. Sisu MD Mircea Cinteza MD, PhD

Dragos Vinereanu MD, PhD

University of Medicine and Pharmacy “Carol Davila“

Department of Cardiology University and Emergency Hospital of Bucharest

050098 Bucharest, Romania E-mail address: [email protected]

doi:10.1016/j.ajem.2008.01.037

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